阿托伐他汀改善自发性高血压大鼠左心功能及其机制研究
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摘要
研究背景：
以往研究表明，他汀类药物(statins)，3′羟基-3′甲基戊二酰辅酶A(3-hydroxy-3-methylglutaryl coenzyme，HMG-COA)还原酶抑制剂，具有多种非调脂作用，能使罹患不同类型心脏疾病的患者受益。近几年，不断地有临床试验和基础研究证据表明，不同种类他汀类药物的使用能有助于心力衰竭患者心功能的提高。细胞内钙稳态对心脏功能非常重要，心肌细胞内钙调节蛋白的异常在心力衰竭发生和发展中起到不可忽视的作用。然而，目前尚不清楚他汀类药物改善心脏功能是否与钙调节蛋白的变化有关。目的：
本课题研究atorvastatin对自发性高血压大鼠(spontaneously hypertensive rat，SHR)左心功能的影响，主要关注药物对心肌组织钙调节蛋白的作用，包括肌浆网Ca~(2+)-ATP酶SERCA(sarcoplasmic reticulum Ca~(2+)-adenosine triphosphatase)，磷酸受纳蛋白PLB(phospholamban)以及磷酸化PLB(phosphorylated PLB)。我们将首次在体研究他汀类药物可否通过影响心肌钙调节蛋白从而促进自发性高血压大鼠左心室功能改善，以阐明对钙调节蛋白的影响是他汀类药物改善左心室功能的可能机制之一。
方法：
8周龄健康雄性SHR以及同周龄雄性Wistar-Kyoto(WKY)大鼠分组后分别予以1 ml蒸馏水，atorvastatin(50 mg/kg／day)，amlodipine(2 mg／kg／day)，或两种药物共用，混合于1 ml蒸馏水中灌胃，每日一次共十周。Amlodipine在此作为血压控制对照药物使用。期间每周测尾动脉收缩压(SBP)，每二周行超声心动图检查，最后以有创血流动力学方法测平均动脉压(MAP)和收缩期和舒张期左室内压最大变化速率(±dp／dt max)。抽取动脉血测血脂水平；以病理学方法检测心肌细胞横径(TDM)和胶原容积分数(CVF)；用Western blot检测心肌组织中SERCA，PLB和磷酸化PLB蛋白水平的表达；测定心肌肌浆网SERCA活性；测定心肌组织羟脯氨酸含量；ELISA法检测心肌组织内炎症因子IL-6，IL-10和TNF-α含量。
结果：
8～18周龄SHR血压逐渐增高，伴有左心室／体重比增加，TDM增大，以及CVF和羟脯氨酸含量增高，这提示SHR大鼠存在明显左心室肥大，心室发生重构。此外，SHR心肌组织内炎症因子水平异常，IL-6和TNF-α浓度增高，IL-10浓度降低。Atorvastatin和amlodipine两药均使SHR血压下降，使其左心室重构指标和炎症因子水平有所改善。与WKY相比，SHR左心室收缩和舒张功能逐渐衰退，心肌组织内SERCA和磷酸化PLB蛋白水平表达减少，SERCA活性亦降低。我们发现使用atorvastatin后SHR左心室功能障碍得到有效控制，并且钙调节蛋白亦向着有利于心功能的方向变化，SERCA和磷酸化PLB表达有所上调，SERCA活性有所增加。
结论：
我们的研究表明，SHR左心室功能障碍的改善很难以atorvastatin和amlodipine在控制血压，改善左心室重构和炎症因子指标等方面的作用来说明。钙调节蛋白的变化可能在该鼠龄段SHR左心室障碍中起了较大作用，atorvastatin对钙调节蛋白的作用是其改善SHR左心室功能的可能机制之一。
Background:
Previous studies have demonstrated that statins,the inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase,have many effects beyond lipid-lowering,which make them of potential benefit in patients with various heart diseases.Recently,statins were shown to improve cardiac function in clinical and experimental studies,andthis protective effect is being confirmed by growing evidence.Also,intracellular Ca~(2+)homeostasis is one of the critical factors responsible for efficient myocardial function,and abnormalities of Ca~(2+)-regulating proteins in myocardium are closely involved in thepathogenesis of cardiac dysfunction.However,it is still unclear whether the beneficialeffect of statins on cardiac function is associated with alterations of Ca~(2+)-regulatingproteins.
Objective:
In this study,we investigated the effect of atorvastatin on cardiac function inspontaneously hypertensive rats(SHRs),focusing in particular on its impact on theexpression of myocardium Ca~(2+)-regulating proteins:sarcoplasmic reticulum Ca~(2+)-adenosine triphosphatase(SERCA),phospholamban(PLB)and its phosphorylated form(phosphorylated PLB).We tried to provide novel in vivo evidence for the potentialmechanism that statin might improve cardiac dysfunction in SHRs via affecting thebehaviors of myocardium Ca~(2+)-regulating proteins.
Methods:
8-week-old male SHRs and Wistar Kyoto rats(WKYs)were given(by gavage for10 weeks)either 1 ml distilled water,atorvastatin(50 mg/kg/day),amlodipine(2mg/kg/day),or both,mixed with 1 ml distilled water.Amlodipine here was used as adrug control for blood pressure.Systolic blood pressure(SBP)was measured weekly bythe tail-cuff method.Echocardiographic measurement was performed biweekly duringthe experiment.Mean arterial pressure(MAP)and the positive and negative firstderivatives of LV pressure(±dp/dt max)were measured by hemodynamic studies.Blood lipid levels were then detected.Pathologic studies was used for evaluatingtransdiameter of cardiomyocyte(TDM)and collagen volume fraction(CVF).Theexpression of SERCA,PLB and phosphorylated PLB protein level were detected byWestern blot analysis.IL-6,IL-10 and TNF-αlevels were quantified,as well as SERCAactivity and hydroxyproline content.
Result:
SBP of SHRs increase gradually at the age of 8～18 week,accompanied withhigher LVW/BW ratio,larger size of TDM,increased myocardium fibrotic infiltrationand hydroxyproline content,which mean cardiac hypertrophy.Also,SHRs haveabnormal inflammatory cytokine concentrations,with higher IL-6 and TNF-αlevels andlower IL-10 level.Both atorvastatin and amlodipine reduce systolic blood pressure,improve LV remodeling and myocardium inflammatory cytokine markers in SHRs.Inaddition,compared to WKYs,SHRs show decreases in gene expression of SERCA andphosphorylated PLB,and reduction in SERCA activity in left ventricular myocardium, as well as gradually reduced cardiac systolic and diastolic function.Furthermore,weshowed that atorvastatin preserved cardiac dysfunction in SHRs,accompanied bypositive alterations in calcium regulatory proteins,with up-regulation in expression ofSERCA and phosphorylated PLB,and with improvement of SERCA activity.
Conclusions:
It can not conclude from our data that the improvement of left ventricular functionin SHRs is due either to the beneficial effects of atorvastatin and amlodipine oninflammatory markers,or reduction in blood pressure,or their effects on remodeling.Alterations in Ca2+-regulating proteins may contribute to the cardiac dysfunction inSHRs,and the HMG-CoA reductase inhibitor atorvastatin modulate the proteinexpression and increase the activity of SERCA,which effectively preserve leftventricular function and may be one of the mechanisms of statins' beneficial effects oncardiac dysfunction in hypertensive rats.
以往研究表明，他汀类药物(statins)，3′羟基-3′甲基戊二酰辅酶A(3-hydroxy-3-methylglutaryl coenzyme，HMG-COA)还原酶抑制剂，具有多种非调脂作用，能使罹患不同类型心脏疾病的患者受益。近几年，不断地有临床试验和基础研究证据表明，不同种类他汀类药物的使用能有助于心力衰竭患者心功能的提高。细胞内钙稳态对心脏功能非常重要，心肌细胞内钙调节蛋白的异常在心力衰竭发生和发展中起到不可忽视的作用。然而，目前尚不清楚他汀类药物改善心脏功能是否与钙调节蛋白的变化有关。目的：
本课题研究atorvastatin对自发性高血压大鼠(spontaneously hypertensive rat，SHR)左心功能的影响，主要关注药物对心肌组织钙调节蛋白的作用，包括肌浆网Ca~(2+)-ATP酶SERCA(sarcoplasmic reticulum Ca~(2+)-adenosine triphosphatase)，磷酸受纳蛋白PLB(phospholamban)以及磷酸化PLB(phosphorylated PLB)。我们将首次在体研究他汀类药物可否通过影响心肌钙调节蛋白从而促进自发性高血压大鼠左心室功能改善，以阐明对钙调节蛋白的影响是他汀类药物改善左心室功能的可能机制之一。
方法：
8周龄健康雄性SHR以及同周龄雄性Wistar-Kyoto(WKY)大鼠分组后分别予以1 ml蒸馏水，atorvastatin(50 mg/kg／day)，amlodipine(2 mg／kg／day)，或两种药物共用，混合于1 ml蒸馏水中灌胃，每日一次共十周。Amlodipine在此作为血压控制对照药物使用。期间每周测尾动脉收缩压(SBP)，每二周行超声心动图检查，最后以有创血流动力学方法测平均动脉压(MAP)和收缩期和舒张期左室内压最大变化速率(±dp／dt max)。抽取动脉血测血脂水平；以病理学方法检测心肌细胞横径(TDM)和胶原容积分数(CVF)；用Western blot检测心肌组织中SERCA，PLB和磷酸化PLB蛋白水平的表达；测定心肌肌浆网SERCA活性；测定心肌组织羟脯氨酸含量；ELISA法检测心肌组织内炎症因子IL-6，IL-10和TNF-α含量。
结果：
8～18周龄SHR血压逐渐增高，伴有左心室／体重比增加，TDM增大，以及CVF和羟脯氨酸含量增高，这提示SHR大鼠存在明显左心室肥大，心室发生重构。此外，SHR心肌组织内炎症因子水平异常，IL-6和TNF-α浓度增高，IL-10浓度降低。Atorvastatin和amlodipine两药均使SHR血压下降，使其左心室重构指标和炎症因子水平有所改善。与WKY相比，SHR左心室收缩和舒张功能逐渐衰退，心肌组织内SERCA和磷酸化PLB蛋白水平表达减少，SERCA活性亦降低。我们发现使用atorvastatin后SHR左心室功能障碍得到有效控制，并且钙调节蛋白亦向着有利于心功能的方向变化，SERCA和磷酸化PLB表达有所上调，SERCA活性有所增加。
结论：
我们的研究表明，SHR左心室功能障碍的改善很难以atorvastatin和amlodipine在控制血压，改善左心室重构和炎症因子指标等方面的作用来说明。钙调节蛋白的变化可能在该鼠龄段SHR左心室障碍中起了较大作用，atorvastatin对钙调节蛋白的作用是其改善SHR左心室功能的可能机制之一。
Background:
Previous studies have demonstrated that statins,the inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase,have many effects beyond lipid-lowering,which make them of potential benefit in patients with various heart diseases.Recently,statins were shown to improve cardiac function in clinical and experimental studies,andthis protective effect is being confirmed by growing evidence.Also,intracellular Ca~(2+)homeostasis is one of the critical factors responsible for efficient myocardial function,and abnormalities of Ca~(2+)-regulating proteins in myocardium are closely involved in thepathogenesis of cardiac dysfunction.However,it is still unclear whether the beneficialeffect of statins on cardiac function is associated with alterations of Ca~(2+)-regulatingproteins.
Objective:
In this study,we investigated the effect of atorvastatin on cardiac function inspontaneously hypertensive rats(SHRs),focusing in particular on its impact on theexpression of myocardium Ca~(2+)-regulating proteins:sarcoplasmic reticulum Ca~(2+)-adenosine triphosphatase(SERCA),phospholamban(PLB)and its phosphorylated form(phosphorylated PLB).We tried to provide novel in vivo evidence for the potentialmechanism that statin might improve cardiac dysfunction in SHRs via affecting thebehaviors of myocardium Ca~(2+)-regulating proteins.
Methods:
8-week-old male SHRs and Wistar Kyoto rats(WKYs)were given(by gavage for10 weeks)either 1 ml distilled water,atorvastatin(50 mg/kg/day),amlodipine(2mg/kg/day),or both,mixed with 1 ml distilled water.Amlodipine here was used as adrug control for blood pressure.Systolic blood pressure(SBP)was measured weekly bythe tail-cuff method.Echocardiographic measurement was performed biweekly duringthe experiment.Mean arterial pressure(MAP)and the positive and negative firstderivatives of LV pressure(±dp/dt max)were measured by hemodynamic studies.Blood lipid levels were then detected.Pathologic studies was used for evaluatingtransdiameter of cardiomyocyte(TDM)and collagen volume fraction(CVF).Theexpression of SERCA,PLB and phosphorylated PLB protein level were detected byWestern blot analysis.IL-6,IL-10 and TNF-αlevels were quantified,as well as SERCAactivity and hydroxyproline content.
Result:
SBP of SHRs increase gradually at the age of 8～18 week,accompanied withhigher LVW/BW ratio,larger size of TDM,increased myocardium fibrotic infiltrationand hydroxyproline content,which mean cardiac hypertrophy.Also,SHRs haveabnormal inflammatory cytokine concentrations,with higher IL-6 and TNF-αlevels andlower IL-10 level.Both atorvastatin and amlodipine reduce systolic blood pressure,improve LV remodeling and myocardium inflammatory cytokine markers in SHRs.Inaddition,compared to WKYs,SHRs show decreases in gene expression of SERCA andphosphorylated PLB,and reduction in SERCA activity in left ventricular myocardium, as well as gradually reduced cardiac systolic and diastolic function.Furthermore,weshowed that atorvastatin preserved cardiac dysfunction in SHRs,accompanied bypositive alterations in calcium regulatory proteins,with up-regulation in expression ofSERCA and phosphorylated PLB,and with improvement of SERCA activity.
Conclusions:
It can not conclude from our data that the improvement of left ventricular functionin SHRs is due either to the beneficial effects of atorvastatin and amlodipine oninflammatory markers,or reduction in blood pressure,or their effects on remodeling.Alterations in Ca2+-regulating proteins may contribute to the cardiac dysfunction inSHRs,and the HMG-CoA reductase inhibitor atorvastatin modulate the proteinexpression and increase the activity of SERCA,which effectively preserve leftventricular function and may be one of the mechanisms of statins' beneficial effects oncardiac dysfunction in hypertensive rats.
引文
[1] Liao,J K. Beyond lipid lowering:the role of statins in vascular protection. Int J Cardiol,2002,86(1): 5-18.
[2] Akdim F, van Leuven SI, Kastelein JJ, Stroes ES. Pleiotropic effects of statins:stabilization of the vulnerable atherosclerotic plaque? Curr Pharm Des, 2007,13(10):1003-1012.
[3] Wong M, Staszewsky L, Carretta E, Barlera S, Latini R, Chiang YT, Glazer RD,Cohn JN. Signs and symptoms in chronic heart failure: relevance of clinical trial results to point of care-data from Val-HeFT. Eur J Heart Fail, 2006,8(5):502-508.
[4] McMurray JJ. Val-HeFT: do angiotensin-receptor blockers benefit heart failure patients already receiving ACE inhibitor therapy? Nat Clin Pract Cardiovasc Med, 2005,2(3):128-129.
[5] Konstam MA, Neaton JD, Poole-Wilson PA, Pitt B, Segal R, Sharma D, Dasbach EJ, Carides GW, Dickstein K, Riegger G, Camm AJ, Martinez FA, Bradstreet DC,Ikeda LS, Santoro EP; ELITE ⅡInvestigators. Comparison of losartan and captopril on heart failure-related outcomes and symptoms from the losartan heart failure survival study (ELITE Ⅱ). Am Heart J, 2005,150(1):123-131.
[6] Horwich TB, MacLellan WR, Fonarow GC. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol, 2004,43(4):642-648.
[7] Wilt TJ, Davis BR, Meyers DG, Rouleau JL, Sacks FM. Prevalence and correlates of symptomatic peripheral atherosclerosis in individuals with coronary heart disease and cholesterol levels less than 240 mg/dL: baseline results from the Cholesterol and Recurrent Events (CARE) Study. Angiology, 1996,47(6):533-541.
[8] The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med, 1998,339(19):1349-1357.
[9] Scandinavian Simvastatin Survival Study (4S) group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet, 1994,344(8934):1383-1389.
[10] Scandinavian Simvastatin Survival Study (4S) group Design and baseline results of the Scandinavian Simvastatin Survival Study of patients with stable angina and/or previous myocardial infarction. Am J Cardiol, 1993,71(5):393-400.
[11] Vrtovec B, Okrajsek R, Golicnik A, Ferjan M, Starc V, Schlegel TT, Radovancevic B. Atorvastatin therapy may reduce the incidence of sudden cardiac death in patients with advanced chronic heart failure. J Card Fail, 2008,14(2):140-144.
[12] Node K, Fujita M, Kitakaze M, Hori M, Liao JK Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation, 2003,108:839-843.
[13] Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J Am Coll Cardiol, 2006,47:332-337.
[14] Laufs U, Wassmann S, Schackmann S, Heeschen C, B(?)hm M, Nickenig G. Beneficial effects of statins in patients with non-ischemic heart failure. Z Kardiol, 2004,93(2):103-108.
[15] Landmesser U, Engberding N, Bahlmann FH, Schaefer A, Wiencke A, Heineke A, Spiekermann S, Hilfiker-Kleiner D, Templin C, Kotlarz D, Mueller M, Fuchs M, Hornig B, Haller H, Drexler H. Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation, 2004,110:1933-1939.
[16] Van Linthout S, Riad A, Dhayat N, Spillmann F, Du J, Dhayat S, Westermann D,Hilfiker-Kleiner D, Noutsias M, Laufs U, Schultheiss HP, Tsch(?)pe C. Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathyDiabetologia, 2007,50(9): 1977-1986.
[17] Ramasubbu K, Estep J, White DL, Deswal A, Mann DL. Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J Am Coll Cardiol, 2008,51(4):415-426.
[18] Zheng X, Hu SJ. Effects of simvastatin on cardiac performance and expression of sarcoplasmic reticular calcium regulatory proteins in rat heart. Acta Pharmacol Sin, 2005,26(6):696-704.
[19] Masafumi Yano,Yasuhiro Ikeda,Masunori Matsuzaki.Altered intracellular Ca~(2+) handling in heart failure. J Clin.Invest, 2005,115:556-564.
[20] Hajime Kubo, Kenneth B.Margulies, Valentino Piacentino et al.Patients with end-stage congestive heart failure treated with β-adrenergic recaptor antagonists have improved ventricular myocyte calcium regulatory protein abundance. Circulation, 2001,104(9):1012-1018.
[21] Sun YL, Hu SJ, Wang LH et al.Effect of beta-blockers on cardiac function and calcium handling protein in postinfarction heart failure rats. Chest, 2005,128(3):1812-1821.
[22] Collins HL, Loka AM, Dicarlo SE. Daily exercise-induced cardioprotection is associated with changes in calcium regulatory proteins in hypertensive rats. Am J Physiol Heart Circ Physiol, 2005,288(2):H532-H540.
[23] Li SY, Golden KL, Jiang Y et al Inhibition of sarco(endo)plasmic reticulum Ca~(2+) -ATPase differentially regulates contractile function in cardiac myocytes from normotensive and spontaneously hypertensive rats: role of Ca~(2+) regulatory proteins. Cell Biochem Biophys, 2005,42(1):1-12.
[24] Mills GD, Kubo H, Harris DM, et al Phosphorylation of phospholamban at threonine-17 reduces cardiac adrenergic contractile responsiveness in chronic pressure overload-induced hypertrophy. Am J Physiol Heart Circ Physiol, 2006,291(1):H61-H70.
[25] Kokubo M, Uemura A, Matsubara T, et al. Noninvasive evaluation of the time course of change in cardiac function in spontaneously hypertensive rats by echocardiography. Hypertens Res, 2005,28(7):601-609.
[26] Borghi C, Dormi A, Veronesi M, Sangiorgi Z, Gaddi A.Brisighella Heart Study Working Party. Association between different lipid-lowering treatment strategies and blood pressure control in the Brisighella Heart Study. Am Heart J, 2004,148:285-292.
[27] Kanbay M, Yildirir A, Bozbas H, et al. Statin therapy helps to control blood pressure levels in hypertensive, dyslipidemic patients. Renal Failure, 2005,27:297-303.
[28] Ge CJ, Hu SJ, Wu YS, Chen NY. Effects of atorvastatin on vascular remodeling in spontaneously hypertensive rats. J Zhejiang Univ Sci, 2003,4(5):612-615.
[29] Sevilla MA, Voces F, Carr(?)n R, Guerrero EI, Ardanaz N, San Rom(?)n L, Ar(?)valo MA, Montero MJ. Amlodipine decreases fibrosis and cardiac hypertrophy in spontaneously hypertensive rats: persistent effects after withdrawal. Life Sci,2004,75:881-891.
[30] Yamori Y, Lovenberg W. Spontaneously hypertensive rats. Hypertension, 1987,9:113-14.
[31] Lee CS. Management of a spontaneously hypertensive rat breeding colony.Hypertension, 1987,9:18-10.
[32] Kokubo M, Uemura A, Matsubara T, Murohara T. Noninvasive evaluation of the time course of change in cardiac function in spontaneously hypertensive rats by echocardiography. Hypertens Res, 2005,28:601-609.
[33] Christe ME, Rodgers RL. Altered glucose and fatty acid oxidation in hearts of the spontaneously hypertensive rat. J Mol Cell Cardiol, 1994,26(10): 1371-1375.
[34] Lloyd TR, Donnerstein RL. Afterload dependence of echocardiographic left ventricular ejection force determination. Am J Cardiol, 1991,67(9):901-903.
[35] Nishimura H, Kubo S, Nishioka A, Imamura K, Kawamura K, Hasegawa M. Left ventricular diastolic function of spontaneously hypertensive rats and its relationship to structural components of the left ventricle. Clin Sci (Lond), 1985,69(5):571-579.
[36] Brilla CG, Janicki JS, Weber KT. Impaired diastolic function and coronary reserve in genetic hypertension. Role of interstitial fibrosis and medial thickening of intramyocardial coronary arteries. Circ Res, 1991,69(1):107-115.
[37] Tahira Y, Fukuda N, Endo M, Suzuki R, Ikeda Y, Takagi H, Matsumoto K, Kanmatsuse K. Transforming growth factor-beta expression in cardiovascular organs in stroke-prone spontaneously hypertensive rats with the development of hypertension. Hypertens Res, 2002,25(6):911-918.
[38] Van Linthout S, Riad A, Dhayat N, Spillmann F, Du J, Dhayat S, Westermann D, Hilfiker-Kleiner D, Noutsias M, Laufs U, Schultheiss HP, Tsch(?)pe C. Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy. Diabetologia, 2007,50(9):1977-1986.
[39] Riad A, Du J, Stiehl S, Westermann D, Mohr Z, Sobirey M, Doehner W, Adams V, Pauschinger M, Schultheiss HP, Tsch(?)pe C. Low-dose treatment with atorvastatin leads to anti-oxidative and anti-inflammatory effects in diabetes mellitus. Eur J Pharmacol, 2007,569(3):204-211.
[40] Wojnicz R, Wilczek K, Nowalany-Kozielska E, Szygula-Jurkiewicz B, Nowak J, Polo(?)ski L, Dyrbus K, Badzi(?)ski A, Mercik G, Zembala M, Wodniecki J, Rozek MM. Usefulness of atorvastatin in patients with heart failure due to inflammatory dilated cardiomyopathy and elevated cholesterol levels. Am J Cardiol, 2006,97:899-904.
[41] Meyer M, Schillinger W, Pieske B, Holubarsch C, Heilmann C, Posival H, Kuwajima G, Mikoshiba K, Just H, Hasenfuss G. Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation, 1995,92:778-784.
[42] Hasenfuss G, Pieske B. Calcium cycling in congestive heart failure. J Mol Cell Cardiol, 2002,34(8): 951-969.
[43] Houser SR, Margulies KB. Is depressed myocyte contractility centrally involved in heart failure? Circ Res, 2003,92(4):350-358.
[44] Qi M, Shannon TR, Euler DE, Bers DM, Samarel AM. Downregulation of sarcoplasmic reticulum Ca~(2+) -ATPase during progression of left ventricular hypertophy. Am J Phsiol, 1997,272: H2416-2424.
[45] Aoyagi T, Yonekura K, Eto Y, Matsumoto A, Yokoyama I, Sugiura S, Momomura S, Hirata Y, Baker DL, Periasamy M. The sarcoplasmic reticulum Ca~(2+) -ATPase (SERCA2) gene promoter activity is decreased in response to severe left ventricular pressure-overload hypertrophy in rat hearts. J Mol Cell Cardiol, 1999,31(4): 919-926.
[46] Matsui H, MacLennan DH, Alpert NR, et al. Sarcoplasmic reticulum gene expression in pressure overloadd-induced cardiac hypertrophy in rabbit. Am J Phsiol, 1995,268:C252-258.
[47] Zierhut W, Studer R, Laurent D. Left ventricular wall stress and sarcoplasmic reticulum Ca~(2+) -ATPase gene expression in renal hypertensive rats: dose dependent effects of ACE inhibition and AT1-receptor blockade. Cardiovasc Res, 1996,31:758-768.
[48] Arai M, Alpert NR, MacLennan DH, Barton P, Periasamy M. Alterations in sarcoplasmic reticulum gene expression in human failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. Circ Res, 1993,72:463-469.
[49] Del Monte F, Williams E, Lebeche D, Schmidt U, Rosenzweig A, Gwathmey JK, Lewandowski ED, Hajjar RJ. Improvement in survival and cardiac metabolism after gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase in a rat model of heart failure. Circulation, 2001,104:1424-1429.
[50] Maier LS, Wahl-Schott C, Horn W, Weichert S, Pagel C, Wagner S, Dybkova N, Muller OJ, Nabauer M, Franz WM, Pieske B. Increased SR Ca~(2+) cycling contributes to improved contractile performance in SERCA2a-overexpressing transgenic rats. Cardiovasc Res, 2005,67:636-646.
[51] Nef HM, Mollmann H, Skwara W, Bolck B, Schwinger RH, Hamm Ch, Kostin S, Schaper J, Elsasser A . Reduced sarcoplasmic reticulum Ca~(2+)-ATPase activity and dephosphorylated phospholamban contribute to contractile dysfunction in human hibernating myocardium. Mol Cell Biochem, 2006,282:53-63.
[52] Hagemann D, Xiao RP. Dual site phospholamban phosphorylation and its physiological relevance in the heart. Trends Cardiovasc Med, 2002,1 2(2):51-56.
[53] Nagayama T, Hsu S, Zhang M, Koitabashi N, Bedja D, Gabrielson KL, Takimoto E, Kass DA. Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J Am Coll Cardiol, 2009,53(2):207-215.
[54] Sande JB, Sjaastad I, Hoen IB, B(?)kenes J, T(?)nnessen T, Holt E, Lunde PK, Christensen G. Reduced level of serine (16) phosphorylated phospholamban in the failing rat myocardium: a major contributor to reduced SERCA2 activity. Cardiovasc Res, 2002,53:382-391.
[55] Colyer J. Phosphorylation states of phospholamban. Ann N Y Acad Sci, 1998,853:79-91.
[56] Rodr(?)guez-Calvo R, Barroso E, Serrano L, Coll T, S(?)nchez RM, Merlos M, Palomer X, Laguna JC, V(?)zquez-Carrera M. Atorvastatin prevents carbohydrate response element binding protein activation in the fructose-fed rat by activating protein kinase A. Hepatology, 2009,49(1):106-115.
[57] Fuse M, Tanaka T, Shibata T, Yoshida T, Noguchi Y, Misawa N, Yasuda T, Saito Y,Kohn LD, Tatsuno I. Regulation of geranylgeranyl pyrophosphate synthase in the proliferation of rat FRTL-5 cells: involvement of both cAMP-PKA and PI3-AKT pathways. Biochem Biophys Res Commun, 2004,315(4):1147-1153.
[58] Paumelle R, Blanquart C, Briand O, Barbier O, Duhem C, Woerly G,Percevault F, Fruchart JC, Dombrowicz D, Glineur C, Staels B.Acute antiinflammatory properties of statins involve peroxisome proliferator-activated receptor-α via inhibition of the protein kinase C signaling pathway. Circ Res, 2006,98:361-369.
[59] Yasunari K, Maeda K, Minami M, Yoshikawa J. HMG-CoA reductase inhibitors prevent migration of human coronary smooth muscle cells through suppression of increase in oxidative stress. Arterioscler Thromb Vasc Biol, 2001,21(6): 937-942
[60] Carr AN, Schmidt AG, Suzuki Y, del Monte F, Sato Y, Lanner C, Breeden K, Jing SL, Allen PB, Greengard P, Yatani A, Hoit BD, Grupp IL, Hajjar RJ, DePaoli-Roach AA, Kranias EG Type 1 Phosphatase, a Negative Regulator of Cardiac Function. Moll Cell Biol, 2002,22:4124-4135.
[61] Gupta RC, Mishra S, Rastogi S, Imai M, Habib O, Sabbah HN Cardiac SR-coupled PP1 activity and expression are increased and inhibitor 1 protein expression is decreased in failing hearts. Am J Physiol Heart Circ Physiol, 2003,285:H2373-H2381.
[62] Braz JC, Gregory K, Pathak A, Zhao W, Sahin B, Klevitsky R, Kimball TF, Lorenz JN, Nairn AC, Liggett SB, Bodi I, Wang S, Schwartz A, Lakatta EG, DePaoli-Roach AA, Robbins J, Hewett TE, Bibb JA, Westfall MV, Kranias EG, Molkentin JD PKC-α regulates cardiac contractility and propensity toward heart failure. Nat Med, 2004,10:248-254.
[63] Clerk A, Bogoyevitch MA, Fuller SJ, Lazou A, Parker PJ, Sugden PH. Expression of protein kinase C isoforms during cardiac ventricular development. Am J Physiol, 1995,269(3 Pt 2):H1087- H1097.
[64] Rybin VO, Steinberg SF. Protein kinase C isoform expression and regulation in the developing rat heart. Circ Res, 1994,74(2):299-309.
[65] Porter MJ, Heidkamp MC, Scully BT, Patel N, Martin JL, Samarel AM. Isoenzyme-selective regulation of SERCA2 gene expression by protein kinase C in neonatal rat ventricular myocytes. Am J Physiol Cell Physiol, 2003,285:C39-C47.
[66] Tanaka K, Honda M, Takabatake T. Anti-apoptotic effect of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, on cardiac myocytes through protein kinase C activation. Clin Exp Pharmacol Physiol, 2004,31:360-364.
[67] Khan SG, Saxena R, Bickers DR, Mukhtar H, Agarwal R. Inhibition of ras p21 membrane localization and modulation of protein kinase C isozyme expression during regression of chemical carcinogen-induced murine skin tumors by lovastatin. Mol Carcinog, 1995,12(4):205-212.
[1] Akdim F, van Leuven SI, Kastelein JJ, Stroes ES. Pleiotropic effects of statins:stabilization of the vulnerable atherosclerotic plaque? Curr Pharm Des, 2007,13(10):1003-1012.
[2] Nakagami H, Kaneda Y, Ogihara T, Morishita R. Endothelial dysfunction in hyperglycemia as a trigger of atherosclerosis. Curr Diabetes Rev, 2005,1(1):59-63.
[3] Liu T, Li L, Korantzopoulos P, Liu E, Li G. Statin use and development of atrial fibrillation: a systematic review and meta-analysis of randomized clinical trials and observational studies. Int J Cardiol, 2008,126(2):160-170.
[4] Feldstein CA. Statins as antihypertensives. Recent Pat Cardiovasc Drug Discov, 2008,3(2):92-97.
[5] Liao,J K. Beyond lipid lowering:the role of statins in vascular protection.Int J Cardiol, 2002,86(1) :5-l8.
[6] Sarafidis PA, Kanaki AI, Lasaridis AN. Effects of statins on blood pressure: a review of the experimental and clinical evidence. Curr Vasc Pharmacol, 2007,5(2):155-161.
[7] Kurian KC, Rai P, Sankaran S, Jacob B, Chiong J, Miller AB. The effect of statins in heart failure: beyond its cholesterol-lowering effect. J Card Fail, 2006,12(6):473-478.
[8] Tousoulis D, Charakida M, Stefanadi E, Siasos G, Latsios G, Stefanadis C. Statins in heart failure. Beyond the lipid lowering effect. Int J Cardiol, 2007,115(2):144-150.
[9] Lipinski MJ, Abbate A, Fuster V, Vetrovec GW. Drug insight: statins for nonischemic heart failure--evidence and potential mechanisms. Nat Clin Pract Cardiovasc Med, 2007,4(4): 196-205.
[10] Wong M, Staszewsky L, Carretta E, Barlera S, Latini R, Chiang YT, Glazer RD, Cohn JN. Signs and symptoms in chronic heart failure: relevance of clinical trial results to point of care-data from Val-HeFT. Eur J Heart Fail, 2006,8(5):502-8.
[11] McMurray JJ. Val-HeFT: do angiotensin-receptor blockers benefit heart failure patients already receiving ACE inhibitor therapy? Nat Clin Pract Cardiovasc Med, 2005,2(3):128-129.
[12] Konstam MA, Neaton JD, Poole-Wilson PA, Pitt B, Segal R, Sharma D, Dasbach EJ, Carides GW, Dickstein K, Riegger G, Camm AJ, Martinez FA, Bradstreet DC,Ikeda LS, Santoro EP,ELITE ⅡInvestigators. Comparison of losartan and captopril on heart failure-related outcomes and symptoms from the losartan heart failure survival study (ELITE Ⅱ). Am Heart J, 2005,150(1):123-131.
[13] Horwich TB, MacLellan WR, Fonarow GC. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol, 2004,43(4):642-648.
[14] Wilt TJ, Davis BR, Meyers DG, Rouleau JL, Sacks FM. Prevalence and correlates of symptomatic peripheral atherosclerosis in individuals with coronary heart disease and cholesterol levels less than 240 mg/dL: baseline results from the Cholesterol and Recurrent Events (CARE) Study. Angiology, 1996,47(6):533-541.
[15] The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med, 1998,339(19):1349-5137.
[16] Scandinavian Simvastatin Survival Study (4S) group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet, 1994,344(8934): 1383-1389.
[17] Scandinavian Simvastatin Survival Study (4S) group. Design and baseline results of the Scandinavian Simvastatin Survival Study of patients with stable angina and/or previous myocardial infarction. Am J Cardiol, 1993,71(5):393-400.
[18] Vrtovec B, Okrajsek R, Golicnik A, Ferjan M, Starc V, Schlegel TT, Radovancevic B. Atorvastatin therapy may reduce the incidence of sudden cardiac death in patients with advanced chronic heart failure. J Card Fail, 2008,14(2):140-144.
[19] Node K, Fujita M, Kitakaze M, Hori M, Liao JK. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation, 2003,108:839-843.
[20] Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J Am Coll Cardiol, 2006,47:332-337.
[21] Laufs U, Wassmann S, Schackmann S, Heeschen C, B(?)hm M, Nickenig G.Beneficial effects of statins in patients with non-ischemic heart failure. Z Kardiol, 2004,93(2):103-108.
[22] Tsutomu Yamazaki, Issei Komuro, Sumiyo Kudoh, Yunzeng Zou, Ichiro Shiojima,Takehiko Mizuno, Hiroyuki Takano, Yukio Hiroi, Kohjiro Ueki, Kazuyuki Tobe, Takashi Kadowaki, Ryozo Nagai, Yoshio Yazaki. Angiotensin Ⅱpartly mediates mechanical stress-induced cardiac hypertrophy. Circ Res, 1995,77(2):258-265.
[23] Yamazaki T, Komuro I, Kudoh S, Zou Y, Shiojima I, Hiroi Y, Mizuno T, Maemura K, Kurihara H, Aikawa R, Takano H, Yazaki Y. Endothelin-1 is involved in mechanical stress-induced cardiomyocyte hypertrophy. J Biol Chem, 1996 ,271(6):3221-3228.
[24] Wang SM, Tsai YJ, Jiang MJ, Tseng YZ. Studies on the function of rho A protein in cardiac myofibrillogenesis. J Cell Biochem, 1997,66(1):43-53.
[25] Thorburn J, Xu S, Thorburn A. MAP kinase- and Rho-dependent signals interact to regulate gene expression but not actin morphology in cardiac muscle cells. Embo J, 1997,16:1888-1900.
[26] Fuller SJ, Gillespie-Brown J, Sugden PH. Oncogenic src, raf, and ras stimulate a hypertrophic pattern of gene expression and increase cell size in neonatal rat ventricular myocytes. J Biol Chem, 1998,273:18146-18152.
[27] Hunter JJ, Tanaka N, Rockman HA, Ross J, Jr., Chien KR. Ventricular expression of a MLC-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice. J Biol Chem, 1995,270: 23173-23178.
[28] Sah VP, Minamisawa S, Tarn SP, Wu TH, Dorn GW 2nd, Ross J Jr, Chien KR,Brown JH. Cardiac-specific over-expression of RhoA results in sinus and atrioventricular nodal dysfunction and contractile failure. J Clin Invest, 1999,103:1627-1634.
[29] Sussman MA, Welch S, Walker A, Klevitsky R, Hewett TE, Price RL, Schaefer E,Yager K. Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active racl. J Clin Invest, 2000,105(7):875-886.
[30] Sah VP, Hoshijima M, Chien KR, Brown JH. Rho is required for Galphaq and alpha1-adrenergic receptor signaling in cardiomyocytes. Dissociation of Ras and Rho pathways. J Biol Chem, 1996,271:31185-31190.
[31] Van Aelst L, D'Souza-Schorey C. Rho GTPases and signaling networks. Genes Dev, 1997,11:2295-2322.
[32] Hall A. Rho GTPases and the actin cytoskeleton. Science, 1998,279:509-514.
[33] Laufs U, La Fata V, Plutzky J, Liao JK. Up-regulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation, 1998,97:1129-1135.
[34] Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem, 1998,273:24266-24271.
[35] Bell JP, Mosfer SI, Lang D, Donaldson F, Lewis MJ. Vitamin C and quinapril abrogate LVH and endothelial dysfunction in aortic-banded guinea pigs. Am J Physiol Heart Circ Physiol, 2001,281:H1704-H1710.
[36] Date MO, Morita T, Yamashita N, Nishida K, Yamaguchi O, Higuchi Y, Hirotani S, Matsumura Y, Hori M, Tada M, Otsu K. The antioxidant N-2-mercaptopropionyl glycine attenuates left ventricular hypertrophy in an in vivo murine pressure-overload model. J Am Coll Cardiol, 2002,39:907-912.
[37] Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin Ⅱstimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res, 1994,74:1141-1148.
[38] Lee TM,Chou TF,Tsai CH.Association of pravastatin and left ventricular mass in hypercholesterolemic patients: role of 8-iso-prostagalandin F2α formation. J cardiovasc Pharmacol, 2002,40:868-874.
[39] Brown JH,Del Re DP,Sussman MA.The Rac and Rho hall of fame:a decade of hypertrophic singaling hits.Circ Res, 2006,730-742.
[40] Hattori T, Shimokawa H, Higashi M, Hiroki J, Mukai Y, Tsutsui H, Kaibuchi K, Takeshita A. Long-term imhibition of Rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice. Circulation, 2004,109:2234-2239.
[41] Kobayashi N, Horinaka S, Mita S, Nakano S, Honda T, Yoshida K, Kobayashi T, Matsuoka H. Critical role of Rho-kinase pathway for cardiac performance and remodeling in failing rat hearts. Cardiovasc Res, 2002,55:757-767.
[42] Indolfi C, Di Lorenzo E, Perrino C, Stingone AM, Curcio A, Torella D, Cittadini A, Cardone L, Coppola C, Cavuto L, Arcucci O, Sacca L, Avvedimento EV, Chiariello M. Hydroxymethylglutaryl coenzyme Areductase inhibitor simvastatin prevents cardiac hypertrophy induced by pressure overload and inhibits p21ras activation. Circulation, 2002,106:2118-2124.
[43] Martin J,Denver R,Bailey M,Krum H. In vitro inhibitory effects of atorvastatin on cardiac fibroblasts:implications of ventricular remodeling. Clin Exp Pharmacol Physiol, 2005,32:697-701.
[44] Saka M, Obata K, Ichihara S, Cheng XW, Kimata H, Nishizawa T, Noda A, Izawa H, Nagata K, Murohara T, Yokota M. Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure. J Cardiovasc Pharmacol, 2006,47(6):770-779.
[45] Habibi J, Whaley-Connell A, Qazi MA, Hayden MR, Cooper SA, Tramontano A,Thyfault J, Stump C, Ferrario C, Muniyappa R, Sowers JR. Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, decreases cardiac oxidative stress and remodeling in Ren2 transgenic rats. Endocrinology, 2007,148(5):2181-2188.
[46] Sato Y, Takatsu Y, Kataoka K, Yamada T, Taniguchi R, Sasayama S, Matsumori A.Serial circulating concentrations of C-reactive protein, interleukin (IL)-4, and IL-6 in patients with acute left heart decompensation. Clin Cardiol, 1999,22(12):811-813.
[47] Francis SE, Holden H, Holt CM, Duff GW. Interleukin-1 in myocardium and coronary arteries of patients with dilated cardiomyopathy. J Mol Cell Cardiol,1998,30(2):215-223.
[48] Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL.Proinfiammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol, 1996 ,27(5):1201-1206.
[49] Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med, 1990,323(4):236-241.
[50] Tousoulis D, Antoniades C, Vassiliadou C, Toutouza M, Pitsavos C, Tentolouris C,Trikas A, Stefanadis C. Effects of combined administration of low dose atorvastatin and vitamin E on inflammatory markers and endothelial function in patients with heart failure. Eur J Heart Fail, 2005 ,7(7):1126-1132.
[51] Krum H, Ashton E, Reid C, Kalff V, Rogers J, Amarena J, Singh B, Tonkin A. Double-blind, randomized, placebo-controlled study of high-dose HMG CoA reductase inhibitor therapy on ventricular remodeling, pro-inflammatory cytokines and neurohormonal parameters in patients with chronic systolic heart failure. J Card Fail, 2007,13(1):1-7.
[52] Hanada T, Yoshimura A. Regulation of cytokine signaling and inflammation.Cytokine Growth Factor Rev, 2002,13(4-5):413-421.
[53] Bevilacqua MR Endothelial-leukocyte adhesion molecules. Annu Rev Immunol, 1993,11:767-804.
[54] Chung HK, Lee IK, Kang H, Suh JM, Kim H, Park KC, Kim DW, Kim YK, Ro HK, Shong M. Statin inhibits interferon-gamma-induced expression of intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial and smooth muscle cells. Exp Mol Med, 2002,34(6):451-461.
[55] Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med, 2000,6(12):1399-1402.
[56] Tang WH, Francis GS. Neurohormonal upregulation in heart failure. Heart Fail Clin,2005,1(1):1-9.
[57] Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation, 1996,93(5):1043-1065.
[58] Ponikowski P, Anker SD, Chua TP, Szelemej R, Piepoli M, Adamopoulos S, Webb-Peploe K, Harrington D, Banasiak W, Wrabec K, Coats AJ. Depressed heart rate variability as an independent predictor of death in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol, 1997,79(12):1645-1650.
[59] Szab(?) BM, van Veldhuisen DJ, van der Veer N, Brouwer J, De Graeff PA, Crijns HJ. Prognostic value of heart rate variability in chronic congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol, 1997 ,79(7):978-980.
[60] Casolo G, Balli E, Taddei T, Amuhasi J, Gori C. Decreased spontaneous heart rate variability in congestive heart failure. Am J Cardiol, 1989,64(18):1162-1167.
[61] Creager MA. Baroreceptor reflex function in congestive heart failure. Am J Cardiol, 1992 ,69(18):10G-15G.
[62] Pliquett RU, Cornish KG, Zucker IH. Statin therapy restores sympathovagal balance in experimental heart failure. J Appl Physiol, 2003,95(2):700-704.
[63] Pliquett RU, Cornish KG, Peuler JD, Zucker IH. Simvastatin normalizes autonomic neural control in experimental heart failure. Circulation, 2003,107(19):2493-2498.
[64] Riahi S, Christensen JH, Toft E, Skou HA, Schmidt EB. HMG-CoA reductase inhibitors improve heart rate variability in patients with a previous myocardial infarction. Pharmacol Res, 2002,45(6):479-483.
[65] Pehlivanidis AN, Athyros VG, Demitriadis DS, Papageorgiou AA, Bouloukos VJ, Kontopoulos AG.Heart rate variability after long-term treatment with atorvastatin in hypercholesterolaemic patients with or without coronary artery disease.Atherosclerosis, 2001,157(2):463-469.
[66] Melenovsky V, Wichterle D, Simek J, Malik J, Haas T, Ceska R, Malik M. Effect of atorvastatin and fenofibrate on autonomic tone in subjects with combined hyperlipidemia. The American Journal of Cardiology, 2003,92(3):337-341.
[67] Gentlesk PJ, Wiley T, Taylor AJ. A prospective evaluation of the effect of simvastatin on heart rate variability in non-ischemic cardiomyopathy. American Heart Journal, 2005,150(3):478-483.
[68] Hamaad A, Sosin M, Lip GY, Macfadyen RJ. Short-term adjuvant atorvastatin improves frequency domain indices of heart rate variability in stable systolic heart failure. Cardiovasc Drugs Ther, 2005,19(3):183-187.
[69] Vrtovec B, Okrajsek R, Golicnik A, Ferjan M, Starc V, Radovancevic B.Atorvastatin Therapy Increases Heart Rate Variability, Decreases QT Variability, and Shortens QTc Interval Duration in Patients With Advanced Chronic Heart Failure. Journal of Cardiac Failure, 2005,11(9):684-690.
[70] Katircibasi MT, Canatar T, Kocum HT, Erol T, Tekin G, Demircan S, Tekin A, Sezgin AT, Baltali M, Muderrisoglu H. Decreased heart rate recovery in patients with heart failure: effect of fluvastatin therapy. Int Heart J, 2005,46(5):845-854.
[71] Gao L, Wang W, Li YL, Schultz HD, Liu D, Cornish KG, Zucker IH. Simvastatin Therapy Normalizes Sympathetic Neural Control in Experimental Heart Failure.Roles of Angiotensin ⅡType 1 Receptors and NAD(P)H Oxidase. Circulation,2005,112(12):1763-1770.
[72] Gao L, Wang W, Li YL, Schultz HD, Liu D, Cornish KG, Zucker IH. Superoxide Mediates Sympathoexcitation in Heart Failure: Roles of Angiotensin Ⅱ and NAD(P)H Oxidase. Circ Res, 2004,95(9):937-944.
[73] Matsuda T, Toyohira Y, Ueno S, Tsutsui M, Yanagihara N. Simvastatin inhibits catecholamine secretion and synthesis induced by acetylcholine via blocking Na+ and Ca~(2+) influx in bovine adrenal medullary cells. J Pharmacol Exp Ther,2008,327(1):130-136.
[74] Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res, 2000,87:840-844
[75] Harrison DG, Widder J, Grumbach I, Chen W, Weber M, Searles C: Endothelial mechanotransduction, nitric oxide and vascular inflammation. J Intern Med, 2006,259:351-363.
[76] Comini L, Bachetti T, Gaia G, Pasini E, Agnoletti L, Pepi P, Ceconi C, Curello S, Ferrari R.Aorta and skeletal muscle NO synthase expression in experimental heart failure. J Mol Cell Cardiol, 1996,28:2241-2248.
[77] Smith CJ, Sun D, Hoegler C, Roth BS, Zhang X, Zhao G, Xu XB, Kobari Y, Pritchard K Jr, Sessa WC, Hintze TH. Reduced gene expression of vascular endothelial NO synthase and cyclooxygenase-1 in heart failure. Circ Res,1996,78:58-64.
[78] Steinberg D. Low density lipoprotein oxidation and its pathobiological significance. J Biol Chem, 1997,272:20963-20966.
[79] Ross R. Atherosclerosis—an inflammatory disease. N EnglJ Med, 1999,340:115-126.
[80] Podrez EA, Schmitt D, Hoff HF, Hazen SL. Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. J Clin Invest,1999,103:1547-1560.
[81] Zmijewski JW, Moellering DR, Le Goffe C, Landar A, Ramachandran A, Darley-Usmar VM. Oxidized LDLinduces mitochondrially associated reactive oxygen/nitrogen species formation in endothelial cells. Am JPhysiol Heart Circ Physiol,2005,289:H852-H861.
[82] Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE,Harrison DG. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest, 2003,111:1201-1209.
[83] Chin JH, Azhar S, Hoffman BB. Inactivation of endothelial derived relaxing factor by oxidized lipoproteins.J Clin Invest, 1992,89:10-18.
[84] Laufs U, Fata VL, Liao JK. Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J Biol Chem, 1997,272(50):31725-31729.
[85] Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoAreductase inhibitors. Circulation, 1998,97(12):1129-1135.
[86] Laufs U, Marra D, Node K, Liao JK. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1). J Biol Chem, 1999,274(31):21926-21931.
[87] Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC, Walsh K.The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med,2000,6(9):1004-1010.
[88] Harris MB, Blackstone MA, Sood SG, Li C, Goolsby JM, Venema VJ, Kemp BE,Venema RC. Acute activation and phosphorylation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors. Am J Physiol Heart Circ Physiol,2004,287(2):H560- H566.
[89] Mraiche F, Cena J, Das D, Vollrath B. Effects of statins on vascular function of endothelin-1. Br J Pharmacol, 2005,144(5):715-726.
[90] Maczewski M, Maczewska J, Duda M. Hypercholesterolaemia exacerbates ventricular remodelling after myocardial infarction in the rat: role of angiotensin Ⅱtype 1 receptors. Br J Pharmacol, 2008,154(8):1640-1648.
[91] Geft D, Schwartzenberg S, George J. Circulating endothelial progenitor cells in cardiovascular disorders. Expert Rev Cardiovasc Ther, 2008,6(8):1115-1121.
[92] Thum T, Fraccarollo D, Galuppo P, Tsikas D, Frantz S, Ertl G, Bauersachs J. Bone marrow molecular alterationsafter myocardial infarction: Impact on endothelial progenitor cells. Cardiovasc Res, 2006,70:50-60.
[93] Zheng X, Hu SJ . Effects of simvastatin on cardiac performance and expression of sarcoplasmic reticular calcium regulatory proteins in rat heart. Acta Pharmacol Sin, 2005,26:696-704.
[94] Yao L, Chen GP, Lu X, Zheng LR, Mou Y, Hu SJ. Effects of atorvastatin on calcium-regulating proteins: a possible mechanism to repair cardiac dysfunction in spontaneously hypertensive rats. Basic Res Cardiol, 2008 Oct 3. [Epub ahead of print].
[95] Yano M, Ikeda Y, Matsuzaki M. Altered intracellular Ca~(2+) handling in heart failure. J Clin Invest, 2005,115(3):556-564.
[96] Hagemann D, Xiao RP. Dual site phospholamban phosphorylation and its physiological relevance in the heart. Trends Cardiovasc Med, 2002,1 2(2):51-56.
[97] Sande JB, Sjaastad I, Hoen IB, B(?)kenes J, T(?)nnessen T, Holt E, Lunde PK, Christensen G. Reduced level of serine (16) phosphorylated phospholamban in the failing rat myocardium: a major contributor to reduced SERCA2 activity.Cardiovasc Res, 2002,53:382-391.
[98] Nagayama T, Hsu S, Zhang M, Koitabashi N, Bedja D, Gabrielson KL, Takimoto E, Kass DA. Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J Am Coll Cardiol, 2009,53(2):207-215.
[99] Zhang Q, Scholz PM, He Y, Tse J, Weiss HR. Cyclic GMP signaling and regulation of SERCA activity during cardiac myocyte contraction. Cell Calcium, 2005,37(3):259-266.
[100] Colyer J. Phosphorylation states of phospholamban. Ann N Y Acad Sci, 1998, 853:79-91.
[101] Rodr(?)guez-Calvo R, Barroso E, Serrano L, Coll T, S(?)nchez RM, Merlos M, Palomer X, Laguna JC, V(?)zquez-Carrera M. Atorvastatin prevents carbohydrate response element binding protein activation in the fructose-fed rat by activating protein kinase A. Hepatology, 2009,49(1): 106-115.
[102] Fuse M, Tanaka T, Shibata T, Yoshida T, Noguchi Y, Misawa N, Yasuda T, Saito Y, Kohn LD, Tatsuno I. Regulation of geranylgeranyl pyrophosphate synthase in the proliferation of rat FRTL-5 cells: involvement of both cAMP-PKA and PI3-AKT pathways. Biochem Biophys Res Commun, 2004,315(4):1147-1153.
[103] Braz JC, Gregory K, Pathak A, Zhao W, Sahin B, Klevitsky R, Kimball TF, Lorenz JN, Nairn AC, Liggett SB, Bodi I, Wang S, Schwartz A, Lakatta EG,DePaoli-Roach AA, Robbins J, Hewett TE, Bibb JA, Westfall MV, Kranias EG,Molkentin JD PKC-α regulates cardiac contractility and propensity toward heart failure. Nat Med, 2004,10:248-254.
[104] Carr AN, Schmidt AG, Suzuki Y, del Monte F, Sato Y, Lanner C, Breeden K, Jing SL, Allen PB, Greengard P, Yatani A, Hoit BD, Grupp IL, Hajjar RJ,DePaoli-Roach AA, Kranias EG Type 1 Phosphatase, a Negative Regulator of Cardiac Function. Moll Cell Biol, 2002,22:4124-4135.
[105] Gupta RC, Mishra S, Rastogi S, Imai M, Habib O, Sabbah HN Cardiac SR-coupled PP1 activity and expression are increased and inhibitor 1 protein expression is decreased in failing hearts. Am J Physiol Heart Circ Physiol, 2003,285:H2373-H2381.
[106] Paumelle R, Blanquart C, Briand O, Barbier O, Duhem C, Woerly G, Percevault F,Fruchart JC, Dombrowicz D, Glineur C, Staels B. Acute antiinflammatory properties of statins involve peroxisome proliferator-activated receptor-α via inhibition of the protein kinase C signaling pathway. Circ Res, 2006,98:361-369.
[107] Yasunari K, Maeda K, Minami M, Yoshikawa J. HMG-CoA reductase inhibitors prevent migration of human coronary smooth muscle cells through suppression of increase in oxidative stress. Arterioscler Thromb Vasc Biol, 2001,21(6):937-942.
[108] Wollert KC, Yurukova S, Kilic A, Begrow F, Fiedler B, Gambaryan S, Walter U, Lohmann SM, Kuhn M. Increased effects of C-type natriuretic peptide on contractility and calcium regulation in murine hearts overexpressing cyclic GMP-dependent protein kinaseⅠ. Br J Pharmacol, 2003,140(7):1227-1236.
[109] Zhang Q, Scholz PM, Pilzak A, Su J, Weiss HR. Role of phospholamban in cyclic GMP mediated signaling in cardiac myocytes. Cell Physiol Biochem, 2007,20(l-4):157-166.
[110] Su J, Scholz PM, Weiss HR. Differential effects of cGMP produced by soluble and particulate guanylyl cyclase on mouse ventricular myocytes. Exp Biol Med (Maywood), 2005,30(4):242-250.
[111] Chen JC, Huang KC, Lin WW. HMG-CoA reductase inhibitors upregulate heme oxygenase-1 expression in murine RAW264.7 macrophages via ERK, p38 MAPK and protein kinase G pathways. Cell Signal, 2006,18(1):32-39.
[112] Clerk A, Bogoyevitch MA, Fuller SJ, Lazou A, Parker PJ, Sugden PH. Expression of protein kinase C isoforms during cardiac ventricular development. Am J Physiol, 1995,269(3 Pt 2):H1087- H1097.
[113] Rybin VO, Steinberg SF. Protein kinase C isoform expression and regulation in the developing rat heart. Circ Res, 1994,74(2):299-309.
[114] Porter MJ, Heidkamp MC, Scully BT, Patel N, Martin JL, Samarel AM.Isoenzyme-selective regulation of SERCA2 gene expression by protein kin ase C in neonatal rat ventricular myocytes. Am J Physiol Cell Physiol, 2003,285:C39-C47.
[115] Tanaka K, Honda M, Takabatake T. Anti-apoptotic effect of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, on cardiac myocytes through protein kinase C activation. Clin Exp Pharmacol Physiol, 2004,31:360-364.
[116] Khan SG, Saxena R, Bickers DR, Mukhtar H, Agarwal R. Inhibition of ras p21 membrane localization and modulation of protein kinase C isozyme expression during regression of chemical carcinogen-induced murine skin tumors by lovastatin. Mol Carcinog, 1995,12(4):205-212.
[2] Akdim F, van Leuven SI, Kastelein JJ, Stroes ES. Pleiotropic effects of statins:stabilization of the vulnerable atherosclerotic plaque? Curr Pharm Des, 2007,13(10):1003-1012.
[3] Wong M, Staszewsky L, Carretta E, Barlera S, Latini R, Chiang YT, Glazer RD,Cohn JN. Signs and symptoms in chronic heart failure: relevance of clinical trial results to point of care-data from Val-HeFT. Eur J Heart Fail, 2006,8(5):502-508.
[4] McMurray JJ. Val-HeFT: do angiotensin-receptor blockers benefit heart failure patients already receiving ACE inhibitor therapy? Nat Clin Pract Cardiovasc Med, 2005,2(3):128-129.
[5] Konstam MA, Neaton JD, Poole-Wilson PA, Pitt B, Segal R, Sharma D, Dasbach EJ, Carides GW, Dickstein K, Riegger G, Camm AJ, Martinez FA, Bradstreet DC,Ikeda LS, Santoro EP; ELITE ⅡInvestigators. Comparison of losartan and captopril on heart failure-related outcomes and symptoms from the losartan heart failure survival study (ELITE Ⅱ). Am Heart J, 2005,150(1):123-131.
[6] Horwich TB, MacLellan WR, Fonarow GC. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol, 2004,43(4):642-648.
[7] Wilt TJ, Davis BR, Meyers DG, Rouleau JL, Sacks FM. Prevalence and correlates of symptomatic peripheral atherosclerosis in individuals with coronary heart disease and cholesterol levels less than 240 mg/dL: baseline results from the Cholesterol and Recurrent Events (CARE) Study. Angiology, 1996,47(6):533-541.
[8] The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med, 1998,339(19):1349-1357.
[9] Scandinavian Simvastatin Survival Study (4S) group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet, 1994,344(8934):1383-1389.
[10] Scandinavian Simvastatin Survival Study (4S) group Design and baseline results of the Scandinavian Simvastatin Survival Study of patients with stable angina and/or previous myocardial infarction. Am J Cardiol, 1993,71(5):393-400.
[11] Vrtovec B, Okrajsek R, Golicnik A, Ferjan M, Starc V, Schlegel TT, Radovancevic B. Atorvastatin therapy may reduce the incidence of sudden cardiac death in patients with advanced chronic heart failure. J Card Fail, 2008,14(2):140-144.
[12] Node K, Fujita M, Kitakaze M, Hori M, Liao JK Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation, 2003,108:839-843.
[13] Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J Am Coll Cardiol, 2006,47:332-337.
[14] Laufs U, Wassmann S, Schackmann S, Heeschen C, B(?)hm M, Nickenig G. Beneficial effects of statins in patients with non-ischemic heart failure. Z Kardiol, 2004,93(2):103-108.
[15] Landmesser U, Engberding N, Bahlmann FH, Schaefer A, Wiencke A, Heineke A, Spiekermann S, Hilfiker-Kleiner D, Templin C, Kotlarz D, Mueller M, Fuchs M, Hornig B, Haller H, Drexler H. Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation, 2004,110:1933-1939.
[16] Van Linthout S, Riad A, Dhayat N, Spillmann F, Du J, Dhayat S, Westermann D,Hilfiker-Kleiner D, Noutsias M, Laufs U, Schultheiss HP, Tsch(?)pe C. Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathyDiabetologia, 2007,50(9): 1977-1986.
[17] Ramasubbu K, Estep J, White DL, Deswal A, Mann DL. Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J Am Coll Cardiol, 2008,51(4):415-426.
[18] Zheng X, Hu SJ. Effects of simvastatin on cardiac performance and expression of sarcoplasmic reticular calcium regulatory proteins in rat heart. Acta Pharmacol Sin, 2005,26(6):696-704.
[19] Masafumi Yano,Yasuhiro Ikeda,Masunori Matsuzaki.Altered intracellular Ca~(2+) handling in heart failure. J Clin.Invest, 2005,115:556-564.
[20] Hajime Kubo, Kenneth B.Margulies, Valentino Piacentino et al.Patients with end-stage congestive heart failure treated with β-adrenergic recaptor antagonists have improved ventricular myocyte calcium regulatory protein abundance. Circulation, 2001,104(9):1012-1018.
[21] Sun YL, Hu SJ, Wang LH et al.Effect of beta-blockers on cardiac function and calcium handling protein in postinfarction heart failure rats. Chest, 2005,128(3):1812-1821.
[22] Collins HL, Loka AM, Dicarlo SE. Daily exercise-induced cardioprotection is associated with changes in calcium regulatory proteins in hypertensive rats. Am J Physiol Heart Circ Physiol, 2005,288(2):H532-H540.
[23] Li SY, Golden KL, Jiang Y et al Inhibition of sarco(endo)plasmic reticulum Ca~(2+) -ATPase differentially regulates contractile function in cardiac myocytes from normotensive and spontaneously hypertensive rats: role of Ca~(2+) regulatory proteins. Cell Biochem Biophys, 2005,42(1):1-12.
[24] Mills GD, Kubo H, Harris DM, et al Phosphorylation of phospholamban at threonine-17 reduces cardiac adrenergic contractile responsiveness in chronic pressure overload-induced hypertrophy. Am J Physiol Heart Circ Physiol, 2006,291(1):H61-H70.
[25] Kokubo M, Uemura A, Matsubara T, et al. Noninvasive evaluation of the time course of change in cardiac function in spontaneously hypertensive rats by echocardiography. Hypertens Res, 2005,28(7):601-609.
[26] Borghi C, Dormi A, Veronesi M, Sangiorgi Z, Gaddi A.Brisighella Heart Study Working Party. Association between different lipid-lowering treatment strategies and blood pressure control in the Brisighella Heart Study. Am Heart J, 2004,148:285-292.
[27] Kanbay M, Yildirir A, Bozbas H, et al. Statin therapy helps to control blood pressure levels in hypertensive, dyslipidemic patients. Renal Failure, 2005,27:297-303.
[28] Ge CJ, Hu SJ, Wu YS, Chen NY. Effects of atorvastatin on vascular remodeling in spontaneously hypertensive rats. J Zhejiang Univ Sci, 2003,4(5):612-615.
[29] Sevilla MA, Voces F, Carr(?)n R, Guerrero EI, Ardanaz N, San Rom(?)n L, Ar(?)valo MA, Montero MJ. Amlodipine decreases fibrosis and cardiac hypertrophy in spontaneously hypertensive rats: persistent effects after withdrawal. Life Sci,2004,75:881-891.
[30] Yamori Y, Lovenberg W. Spontaneously hypertensive rats. Hypertension, 1987,9:113-14.
[31] Lee CS. Management of a spontaneously hypertensive rat breeding colony.Hypertension, 1987,9:18-10.
[32] Kokubo M, Uemura A, Matsubara T, Murohara T. Noninvasive evaluation of the time course of change in cardiac function in spontaneously hypertensive rats by echocardiography. Hypertens Res, 2005,28:601-609.
[33] Christe ME, Rodgers RL. Altered glucose and fatty acid oxidation in hearts of the spontaneously hypertensive rat. J Mol Cell Cardiol, 1994,26(10): 1371-1375.
[34] Lloyd TR, Donnerstein RL. Afterload dependence of echocardiographic left ventricular ejection force determination. Am J Cardiol, 1991,67(9):901-903.
[35] Nishimura H, Kubo S, Nishioka A, Imamura K, Kawamura K, Hasegawa M. Left ventricular diastolic function of spontaneously hypertensive rats and its relationship to structural components of the left ventricle. Clin Sci (Lond), 1985,69(5):571-579.
[36] Brilla CG, Janicki JS, Weber KT. Impaired diastolic function and coronary reserve in genetic hypertension. Role of interstitial fibrosis and medial thickening of intramyocardial coronary arteries. Circ Res, 1991,69(1):107-115.
[37] Tahira Y, Fukuda N, Endo M, Suzuki R, Ikeda Y, Takagi H, Matsumoto K, Kanmatsuse K. Transforming growth factor-beta expression in cardiovascular organs in stroke-prone spontaneously hypertensive rats with the development of hypertension. Hypertens Res, 2002,25(6):911-918.
[38] Van Linthout S, Riad A, Dhayat N, Spillmann F, Du J, Dhayat S, Westermann D, Hilfiker-Kleiner D, Noutsias M, Laufs U, Schultheiss HP, Tsch(?)pe C. Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy. Diabetologia, 2007,50(9):1977-1986.
[39] Riad A, Du J, Stiehl S, Westermann D, Mohr Z, Sobirey M, Doehner W, Adams V, Pauschinger M, Schultheiss HP, Tsch(?)pe C. Low-dose treatment with atorvastatin leads to anti-oxidative and anti-inflammatory effects in diabetes mellitus. Eur J Pharmacol, 2007,569(3):204-211.
[40] Wojnicz R, Wilczek K, Nowalany-Kozielska E, Szygula-Jurkiewicz B, Nowak J, Polo(?)ski L, Dyrbus K, Badzi(?)ski A, Mercik G, Zembala M, Wodniecki J, Rozek MM. Usefulness of atorvastatin in patients with heart failure due to inflammatory dilated cardiomyopathy and elevated cholesterol levels. Am J Cardiol, 2006,97:899-904.
[41] Meyer M, Schillinger W, Pieske B, Holubarsch C, Heilmann C, Posival H, Kuwajima G, Mikoshiba K, Just H, Hasenfuss G. Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation, 1995,92:778-784.
[42] Hasenfuss G, Pieske B. Calcium cycling in congestive heart failure. J Mol Cell Cardiol, 2002,34(8): 951-969.
[43] Houser SR, Margulies KB. Is depressed myocyte contractility centrally involved in heart failure? Circ Res, 2003,92(4):350-358.
[44] Qi M, Shannon TR, Euler DE, Bers DM, Samarel AM. Downregulation of sarcoplasmic reticulum Ca~(2+) -ATPase during progression of left ventricular hypertophy. Am J Phsiol, 1997,272: H2416-2424.
[45] Aoyagi T, Yonekura K, Eto Y, Matsumoto A, Yokoyama I, Sugiura S, Momomura S, Hirata Y, Baker DL, Periasamy M. The sarcoplasmic reticulum Ca~(2+) -ATPase (SERCA2) gene promoter activity is decreased in response to severe left ventricular pressure-overload hypertrophy in rat hearts. J Mol Cell Cardiol, 1999,31(4): 919-926.
[46] Matsui H, MacLennan DH, Alpert NR, et al. Sarcoplasmic reticulum gene expression in pressure overloadd-induced cardiac hypertrophy in rabbit. Am J Phsiol, 1995,268:C252-258.
[47] Zierhut W, Studer R, Laurent D. Left ventricular wall stress and sarcoplasmic reticulum Ca~(2+) -ATPase gene expression in renal hypertensive rats: dose dependent effects of ACE inhibition and AT1-receptor blockade. Cardiovasc Res, 1996,31:758-768.
[48] Arai M, Alpert NR, MacLennan DH, Barton P, Periasamy M. Alterations in sarcoplasmic reticulum gene expression in human failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. Circ Res, 1993,72:463-469.
[49] Del Monte F, Williams E, Lebeche D, Schmidt U, Rosenzweig A, Gwathmey JK, Lewandowski ED, Hajjar RJ. Improvement in survival and cardiac metabolism after gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase in a rat model of heart failure. Circulation, 2001,104:1424-1429.
[50] Maier LS, Wahl-Schott C, Horn W, Weichert S, Pagel C, Wagner S, Dybkova N, Muller OJ, Nabauer M, Franz WM, Pieske B. Increased SR Ca~(2+) cycling contributes to improved contractile performance in SERCA2a-overexpressing transgenic rats. Cardiovasc Res, 2005,67:636-646.
[51] Nef HM, Mollmann H, Skwara W, Bolck B, Schwinger RH, Hamm Ch, Kostin S, Schaper J, Elsasser A . Reduced sarcoplasmic reticulum Ca~(2+)-ATPase activity and dephosphorylated phospholamban contribute to contractile dysfunction in human hibernating myocardium. Mol Cell Biochem, 2006,282:53-63.
[52] Hagemann D, Xiao RP. Dual site phospholamban phosphorylation and its physiological relevance in the heart. Trends Cardiovasc Med, 2002,1 2(2):51-56.
[53] Nagayama T, Hsu S, Zhang M, Koitabashi N, Bedja D, Gabrielson KL, Takimoto E, Kass DA. Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J Am Coll Cardiol, 2009,53(2):207-215.
[54] Sande JB, Sjaastad I, Hoen IB, B(?)kenes J, T(?)nnessen T, Holt E, Lunde PK, Christensen G. Reduced level of serine (16) phosphorylated phospholamban in the failing rat myocardium: a major contributor to reduced SERCA2 activity. Cardiovasc Res, 2002,53:382-391.
[55] Colyer J. Phosphorylation states of phospholamban. Ann N Y Acad Sci, 1998,853:79-91.
[56] Rodr(?)guez-Calvo R, Barroso E, Serrano L, Coll T, S(?)nchez RM, Merlos M, Palomer X, Laguna JC, V(?)zquez-Carrera M. Atorvastatin prevents carbohydrate response element binding protein activation in the fructose-fed rat by activating protein kinase A. Hepatology, 2009,49(1):106-115.
[57] Fuse M, Tanaka T, Shibata T, Yoshida T, Noguchi Y, Misawa N, Yasuda T, Saito Y,Kohn LD, Tatsuno I. Regulation of geranylgeranyl pyrophosphate synthase in the proliferation of rat FRTL-5 cells: involvement of both cAMP-PKA and PI3-AKT pathways. Biochem Biophys Res Commun, 2004,315(4):1147-1153.
[58] Paumelle R, Blanquart C, Briand O, Barbier O, Duhem C, Woerly G,Percevault F, Fruchart JC, Dombrowicz D, Glineur C, Staels B.Acute antiinflammatory properties of statins involve peroxisome proliferator-activated receptor-α via inhibition of the protein kinase C signaling pathway. Circ Res, 2006,98:361-369.
[59] Yasunari K, Maeda K, Minami M, Yoshikawa J. HMG-CoA reductase inhibitors prevent migration of human coronary smooth muscle cells through suppression of increase in oxidative stress. Arterioscler Thromb Vasc Biol, 2001,21(6): 937-942
[60] Carr AN, Schmidt AG, Suzuki Y, del Monte F, Sato Y, Lanner C, Breeden K, Jing SL, Allen PB, Greengard P, Yatani A, Hoit BD, Grupp IL, Hajjar RJ, DePaoli-Roach AA, Kranias EG Type 1 Phosphatase, a Negative Regulator of Cardiac Function. Moll Cell Biol, 2002,22:4124-4135.
[61] Gupta RC, Mishra S, Rastogi S, Imai M, Habib O, Sabbah HN Cardiac SR-coupled PP1 activity and expression are increased and inhibitor 1 protein expression is decreased in failing hearts. Am J Physiol Heart Circ Physiol, 2003,285:H2373-H2381.
[62] Braz JC, Gregory K, Pathak A, Zhao W, Sahin B, Klevitsky R, Kimball TF, Lorenz JN, Nairn AC, Liggett SB, Bodi I, Wang S, Schwartz A, Lakatta EG, DePaoli-Roach AA, Robbins J, Hewett TE, Bibb JA, Westfall MV, Kranias EG, Molkentin JD PKC-α regulates cardiac contractility and propensity toward heart failure. Nat Med, 2004,10:248-254.
[63] Clerk A, Bogoyevitch MA, Fuller SJ, Lazou A, Parker PJ, Sugden PH. Expression of protein kinase C isoforms during cardiac ventricular development. Am J Physiol, 1995,269(3 Pt 2):H1087- H1097.
[64] Rybin VO, Steinberg SF. Protein kinase C isoform expression and regulation in the developing rat heart. Circ Res, 1994,74(2):299-309.
[65] Porter MJ, Heidkamp MC, Scully BT, Patel N, Martin JL, Samarel AM. Isoenzyme-selective regulation of SERCA2 gene expression by protein kinase C in neonatal rat ventricular myocytes. Am J Physiol Cell Physiol, 2003,285:C39-C47.
[66] Tanaka K, Honda M, Takabatake T. Anti-apoptotic effect of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, on cardiac myocytes through protein kinase C activation. Clin Exp Pharmacol Physiol, 2004,31:360-364.
[67] Khan SG, Saxena R, Bickers DR, Mukhtar H, Agarwal R. Inhibition of ras p21 membrane localization and modulation of protein kinase C isozyme expression during regression of chemical carcinogen-induced murine skin tumors by lovastatin. Mol Carcinog, 1995,12(4):205-212.
[1] Akdim F, van Leuven SI, Kastelein JJ, Stroes ES. Pleiotropic effects of statins:stabilization of the vulnerable atherosclerotic plaque? Curr Pharm Des, 2007,13(10):1003-1012.
[2] Nakagami H, Kaneda Y, Ogihara T, Morishita R. Endothelial dysfunction in hyperglycemia as a trigger of atherosclerosis. Curr Diabetes Rev, 2005,1(1):59-63.
[3] Liu T, Li L, Korantzopoulos P, Liu E, Li G. Statin use and development of atrial fibrillation: a systematic review and meta-analysis of randomized clinical trials and observational studies. Int J Cardiol, 2008,126(2):160-170.
[4] Feldstein CA. Statins as antihypertensives. Recent Pat Cardiovasc Drug Discov, 2008,3(2):92-97.
[5] Liao,J K. Beyond lipid lowering:the role of statins in vascular protection.Int J Cardiol, 2002,86(1) :5-l8.
[6] Sarafidis PA, Kanaki AI, Lasaridis AN. Effects of statins on blood pressure: a review of the experimental and clinical evidence. Curr Vasc Pharmacol, 2007,5(2):155-161.
[7] Kurian KC, Rai P, Sankaran S, Jacob B, Chiong J, Miller AB. The effect of statins in heart failure: beyond its cholesterol-lowering effect. J Card Fail, 2006,12(6):473-478.
[8] Tousoulis D, Charakida M, Stefanadi E, Siasos G, Latsios G, Stefanadis C. Statins in heart failure. Beyond the lipid lowering effect. Int J Cardiol, 2007,115(2):144-150.
[9] Lipinski MJ, Abbate A, Fuster V, Vetrovec GW. Drug insight: statins for nonischemic heart failure--evidence and potential mechanisms. Nat Clin Pract Cardiovasc Med, 2007,4(4): 196-205.
[10] Wong M, Staszewsky L, Carretta E, Barlera S, Latini R, Chiang YT, Glazer RD, Cohn JN. Signs and symptoms in chronic heart failure: relevance of clinical trial results to point of care-data from Val-HeFT. Eur J Heart Fail, 2006,8(5):502-8.
[11] McMurray JJ. Val-HeFT: do angiotensin-receptor blockers benefit heart failure patients already receiving ACE inhibitor therapy? Nat Clin Pract Cardiovasc Med, 2005,2(3):128-129.
[12] Konstam MA, Neaton JD, Poole-Wilson PA, Pitt B, Segal R, Sharma D, Dasbach EJ, Carides GW, Dickstein K, Riegger G, Camm AJ, Martinez FA, Bradstreet DC,Ikeda LS, Santoro EP,ELITE ⅡInvestigators. Comparison of losartan and captopril on heart failure-related outcomes and symptoms from the losartan heart failure survival study (ELITE Ⅱ). Am Heart J, 2005,150(1):123-131.
[13] Horwich TB, MacLellan WR, Fonarow GC. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol, 2004,43(4):642-648.
[14] Wilt TJ, Davis BR, Meyers DG, Rouleau JL, Sacks FM. Prevalence and correlates of symptomatic peripheral atherosclerosis in individuals with coronary heart disease and cholesterol levels less than 240 mg/dL: baseline results from the Cholesterol and Recurrent Events (CARE) Study. Angiology, 1996,47(6):533-541.
[15] The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med, 1998,339(19):1349-5137.
[16] Scandinavian Simvastatin Survival Study (4S) group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet, 1994,344(8934): 1383-1389.
[17] Scandinavian Simvastatin Survival Study (4S) group. Design and baseline results of the Scandinavian Simvastatin Survival Study of patients with stable angina and/or previous myocardial infarction. Am J Cardiol, 1993,71(5):393-400.
[18] Vrtovec B, Okrajsek R, Golicnik A, Ferjan M, Starc V, Schlegel TT, Radovancevic B. Atorvastatin therapy may reduce the incidence of sudden cardiac death in patients with advanced chronic heart failure. J Card Fail, 2008,14(2):140-144.
[19] Node K, Fujita M, Kitakaze M, Hori M, Liao JK. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation, 2003,108:839-843.
[20] Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J Am Coll Cardiol, 2006,47:332-337.
[21] Laufs U, Wassmann S, Schackmann S, Heeschen C, B(?)hm M, Nickenig G.Beneficial effects of statins in patients with non-ischemic heart failure. Z Kardiol, 2004,93(2):103-108.
[22] Tsutomu Yamazaki, Issei Komuro, Sumiyo Kudoh, Yunzeng Zou, Ichiro Shiojima,Takehiko Mizuno, Hiroyuki Takano, Yukio Hiroi, Kohjiro Ueki, Kazuyuki Tobe, Takashi Kadowaki, Ryozo Nagai, Yoshio Yazaki. Angiotensin Ⅱpartly mediates mechanical stress-induced cardiac hypertrophy. Circ Res, 1995,77(2):258-265.
[23] Yamazaki T, Komuro I, Kudoh S, Zou Y, Shiojima I, Hiroi Y, Mizuno T, Maemura K, Kurihara H, Aikawa R, Takano H, Yazaki Y. Endothelin-1 is involved in mechanical stress-induced cardiomyocyte hypertrophy. J Biol Chem, 1996 ,271(6):3221-3228.
[24] Wang SM, Tsai YJ, Jiang MJ, Tseng YZ. Studies on the function of rho A protein in cardiac myofibrillogenesis. J Cell Biochem, 1997,66(1):43-53.
[25] Thorburn J, Xu S, Thorburn A. MAP kinase- and Rho-dependent signals interact to regulate gene expression but not actin morphology in cardiac muscle cells. Embo J, 1997,16:1888-1900.
[26] Fuller SJ, Gillespie-Brown J, Sugden PH. Oncogenic src, raf, and ras stimulate a hypertrophic pattern of gene expression and increase cell size in neonatal rat ventricular myocytes. J Biol Chem, 1998,273:18146-18152.
[27] Hunter JJ, Tanaka N, Rockman HA, Ross J, Jr., Chien KR. Ventricular expression of a MLC-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice. J Biol Chem, 1995,270: 23173-23178.
[28] Sah VP, Minamisawa S, Tarn SP, Wu TH, Dorn GW 2nd, Ross J Jr, Chien KR,Brown JH. Cardiac-specific over-expression of RhoA results in sinus and atrioventricular nodal dysfunction and contractile failure. J Clin Invest, 1999,103:1627-1634.
[29] Sussman MA, Welch S, Walker A, Klevitsky R, Hewett TE, Price RL, Schaefer E,Yager K. Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active racl. J Clin Invest, 2000,105(7):875-886.
[30] Sah VP, Hoshijima M, Chien KR, Brown JH. Rho is required for Galphaq and alpha1-adrenergic receptor signaling in cardiomyocytes. Dissociation of Ras and Rho pathways. J Biol Chem, 1996,271:31185-31190.
[31] Van Aelst L, D'Souza-Schorey C. Rho GTPases and signaling networks. Genes Dev, 1997,11:2295-2322.
[32] Hall A. Rho GTPases and the actin cytoskeleton. Science, 1998,279:509-514.
[33] Laufs U, La Fata V, Plutzky J, Liao JK. Up-regulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation, 1998,97:1129-1135.
[34] Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem, 1998,273:24266-24271.
[35] Bell JP, Mosfer SI, Lang D, Donaldson F, Lewis MJ. Vitamin C and quinapril abrogate LVH and endothelial dysfunction in aortic-banded guinea pigs. Am J Physiol Heart Circ Physiol, 2001,281:H1704-H1710.
[36] Date MO, Morita T, Yamashita N, Nishida K, Yamaguchi O, Higuchi Y, Hirotani S, Matsumura Y, Hori M, Tada M, Otsu K. The antioxidant N-2-mercaptopropionyl glycine attenuates left ventricular hypertrophy in an in vivo murine pressure-overload model. J Am Coll Cardiol, 2002,39:907-912.
[37] Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin Ⅱstimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res, 1994,74:1141-1148.
[38] Lee TM,Chou TF,Tsai CH.Association of pravastatin and left ventricular mass in hypercholesterolemic patients: role of 8-iso-prostagalandin F2α formation. J cardiovasc Pharmacol, 2002,40:868-874.
[39] Brown JH,Del Re DP,Sussman MA.The Rac and Rho hall of fame:a decade of hypertrophic singaling hits.Circ Res, 2006,730-742.
[40] Hattori T, Shimokawa H, Higashi M, Hiroki J, Mukai Y, Tsutsui H, Kaibuchi K, Takeshita A. Long-term imhibition of Rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice. Circulation, 2004,109:2234-2239.
[41] Kobayashi N, Horinaka S, Mita S, Nakano S, Honda T, Yoshida K, Kobayashi T, Matsuoka H. Critical role of Rho-kinase pathway for cardiac performance and remodeling in failing rat hearts. Cardiovasc Res, 2002,55:757-767.
[42] Indolfi C, Di Lorenzo E, Perrino C, Stingone AM, Curcio A, Torella D, Cittadini A, Cardone L, Coppola C, Cavuto L, Arcucci O, Sacca L, Avvedimento EV, Chiariello M. Hydroxymethylglutaryl coenzyme Areductase inhibitor simvastatin prevents cardiac hypertrophy induced by pressure overload and inhibits p21ras activation. Circulation, 2002,106:2118-2124.
[43] Martin J,Denver R,Bailey M,Krum H. In vitro inhibitory effects of atorvastatin on cardiac fibroblasts:implications of ventricular remodeling. Clin Exp Pharmacol Physiol, 2005,32:697-701.
[44] Saka M, Obata K, Ichihara S, Cheng XW, Kimata H, Nishizawa T, Noda A, Izawa H, Nagata K, Murohara T, Yokota M. Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure. J Cardiovasc Pharmacol, 2006,47(6):770-779.
[45] Habibi J, Whaley-Connell A, Qazi MA, Hayden MR, Cooper SA, Tramontano A,Thyfault J, Stump C, Ferrario C, Muniyappa R, Sowers JR. Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, decreases cardiac oxidative stress and remodeling in Ren2 transgenic rats. Endocrinology, 2007,148(5):2181-2188.
[46] Sato Y, Takatsu Y, Kataoka K, Yamada T, Taniguchi R, Sasayama S, Matsumori A.Serial circulating concentrations of C-reactive protein, interleukin (IL)-4, and IL-6 in patients with acute left heart decompensation. Clin Cardiol, 1999,22(12):811-813.
[47] Francis SE, Holden H, Holt CM, Duff GW. Interleukin-1 in myocardium and coronary arteries of patients with dilated cardiomyopathy. J Mol Cell Cardiol,1998,30(2):215-223.
[48] Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL.Proinfiammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol, 1996 ,27(5):1201-1206.
[49] Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med, 1990,323(4):236-241.
[50] Tousoulis D, Antoniades C, Vassiliadou C, Toutouza M, Pitsavos C, Tentolouris C,Trikas A, Stefanadis C. Effects of combined administration of low dose atorvastatin and vitamin E on inflammatory markers and endothelial function in patients with heart failure. Eur J Heart Fail, 2005 ,7(7):1126-1132.
[51] Krum H, Ashton E, Reid C, Kalff V, Rogers J, Amarena J, Singh B, Tonkin A. Double-blind, randomized, placebo-controlled study of high-dose HMG CoA reductase inhibitor therapy on ventricular remodeling, pro-inflammatory cytokines and neurohormonal parameters in patients with chronic systolic heart failure. J Card Fail, 2007,13(1):1-7.
[52] Hanada T, Yoshimura A. Regulation of cytokine signaling and inflammation.Cytokine Growth Factor Rev, 2002,13(4-5):413-421.
[53] Bevilacqua MR Endothelial-leukocyte adhesion molecules. Annu Rev Immunol, 1993,11:767-804.
[54] Chung HK, Lee IK, Kang H, Suh JM, Kim H, Park KC, Kim DW, Kim YK, Ro HK, Shong M. Statin inhibits interferon-gamma-induced expression of intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial and smooth muscle cells. Exp Mol Med, 2002,34(6):451-461.
[55] Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med, 2000,6(12):1399-1402.
[56] Tang WH, Francis GS. Neurohormonal upregulation in heart failure. Heart Fail Clin,2005,1(1):1-9.
[57] Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation, 1996,93(5):1043-1065.
[58] Ponikowski P, Anker SD, Chua TP, Szelemej R, Piepoli M, Adamopoulos S, Webb-Peploe K, Harrington D, Banasiak W, Wrabec K, Coats AJ. Depressed heart rate variability as an independent predictor of death in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol, 1997,79(12):1645-1650.
[59] Szab(?) BM, van Veldhuisen DJ, van der Veer N, Brouwer J, De Graeff PA, Crijns HJ. Prognostic value of heart rate variability in chronic congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol, 1997 ,79(7):978-980.
[60] Casolo G, Balli E, Taddei T, Amuhasi J, Gori C. Decreased spontaneous heart rate variability in congestive heart failure. Am J Cardiol, 1989,64(18):1162-1167.
[61] Creager MA. Baroreceptor reflex function in congestive heart failure. Am J Cardiol, 1992 ,69(18):10G-15G.
[62] Pliquett RU, Cornish KG, Zucker IH. Statin therapy restores sympathovagal balance in experimental heart failure. J Appl Physiol, 2003,95(2):700-704.
[63] Pliquett RU, Cornish KG, Peuler JD, Zucker IH. Simvastatin normalizes autonomic neural control in experimental heart failure. Circulation, 2003,107(19):2493-2498.
[64] Riahi S, Christensen JH, Toft E, Skou HA, Schmidt EB. HMG-CoA reductase inhibitors improve heart rate variability in patients with a previous myocardial infarction. Pharmacol Res, 2002,45(6):479-483.
[65] Pehlivanidis AN, Athyros VG, Demitriadis DS, Papageorgiou AA, Bouloukos VJ, Kontopoulos AG.Heart rate variability after long-term treatment with atorvastatin in hypercholesterolaemic patients with or without coronary artery disease.Atherosclerosis, 2001,157(2):463-469.
[66] Melenovsky V, Wichterle D, Simek J, Malik J, Haas T, Ceska R, Malik M. Effect of atorvastatin and fenofibrate on autonomic tone in subjects with combined hyperlipidemia. The American Journal of Cardiology, 2003,92(3):337-341.
[67] Gentlesk PJ, Wiley T, Taylor AJ. A prospective evaluation of the effect of simvastatin on heart rate variability in non-ischemic cardiomyopathy. American Heart Journal, 2005,150(3):478-483.
[68] Hamaad A, Sosin M, Lip GY, Macfadyen RJ. Short-term adjuvant atorvastatin improves frequency domain indices of heart rate variability in stable systolic heart failure. Cardiovasc Drugs Ther, 2005,19(3):183-187.
[69] Vrtovec B, Okrajsek R, Golicnik A, Ferjan M, Starc V, Radovancevic B.Atorvastatin Therapy Increases Heart Rate Variability, Decreases QT Variability, and Shortens QTc Interval Duration in Patients With Advanced Chronic Heart Failure. Journal of Cardiac Failure, 2005,11(9):684-690.
[70] Katircibasi MT, Canatar T, Kocum HT, Erol T, Tekin G, Demircan S, Tekin A, Sezgin AT, Baltali M, Muderrisoglu H. Decreased heart rate recovery in patients with heart failure: effect of fluvastatin therapy. Int Heart J, 2005,46(5):845-854.
[71] Gao L, Wang W, Li YL, Schultz HD, Liu D, Cornish KG, Zucker IH. Simvastatin Therapy Normalizes Sympathetic Neural Control in Experimental Heart Failure.Roles of Angiotensin ⅡType 1 Receptors and NAD(P)H Oxidase. Circulation,2005,112(12):1763-1770.
[72] Gao L, Wang W, Li YL, Schultz HD, Liu D, Cornish KG, Zucker IH. Superoxide Mediates Sympathoexcitation in Heart Failure: Roles of Angiotensin Ⅱ and NAD(P)H Oxidase. Circ Res, 2004,95(9):937-944.
[73] Matsuda T, Toyohira Y, Ueno S, Tsutsui M, Yanagihara N. Simvastatin inhibits catecholamine secretion and synthesis induced by acetylcholine via blocking Na+ and Ca~(2+) influx in bovine adrenal medullary cells. J Pharmacol Exp Ther,2008,327(1):130-136.
[74] Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res, 2000,87:840-844
[75] Harrison DG, Widder J, Grumbach I, Chen W, Weber M, Searles C: Endothelial mechanotransduction, nitric oxide and vascular inflammation. J Intern Med, 2006,259:351-363.
[76] Comini L, Bachetti T, Gaia G, Pasini E, Agnoletti L, Pepi P, Ceconi C, Curello S, Ferrari R.Aorta and skeletal muscle NO synthase expression in experimental heart failure. J Mol Cell Cardiol, 1996,28:2241-2248.
[77] Smith CJ, Sun D, Hoegler C, Roth BS, Zhang X, Zhao G, Xu XB, Kobari Y, Pritchard K Jr, Sessa WC, Hintze TH. Reduced gene expression of vascular endothelial NO synthase and cyclooxygenase-1 in heart failure. Circ Res,1996,78:58-64.
[78] Steinberg D. Low density lipoprotein oxidation and its pathobiological significance. J Biol Chem, 1997,272:20963-20966.
[79] Ross R. Atherosclerosis—an inflammatory disease. N EnglJ Med, 1999,340:115-126.
[80] Podrez EA, Schmitt D, Hoff HF, Hazen SL. Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. J Clin Invest,1999,103:1547-1560.
[81] Zmijewski JW, Moellering DR, Le Goffe C, Landar A, Ramachandran A, Darley-Usmar VM. Oxidized LDLinduces mitochondrially associated reactive oxygen/nitrogen species formation in endothelial cells. Am JPhysiol Heart Circ Physiol,2005,289:H852-H861.
[82] Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE,Harrison DG. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest, 2003,111:1201-1209.
[83] Chin JH, Azhar S, Hoffman BB. Inactivation of endothelial derived relaxing factor by oxidized lipoproteins.J Clin Invest, 1992,89:10-18.
[84] Laufs U, Fata VL, Liao JK. Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J Biol Chem, 1997,272(50):31725-31729.
[85] Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoAreductase inhibitors. Circulation, 1998,97(12):1129-1135.
[86] Laufs U, Marra D, Node K, Liao JK. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1). J Biol Chem, 1999,274(31):21926-21931.
[87] Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC, Walsh K.The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med,2000,6(9):1004-1010.
[88] Harris MB, Blackstone MA, Sood SG, Li C, Goolsby JM, Venema VJ, Kemp BE,Venema RC. Acute activation and phosphorylation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors. Am J Physiol Heart Circ Physiol,2004,287(2):H560- H566.
[89] Mraiche F, Cena J, Das D, Vollrath B. Effects of statins on vascular function of endothelin-1. Br J Pharmacol, 2005,144(5):715-726.
[90] Maczewski M, Maczewska J, Duda M. Hypercholesterolaemia exacerbates ventricular remodelling after myocardial infarction in the rat: role of angiotensin Ⅱtype 1 receptors. Br J Pharmacol, 2008,154(8):1640-1648.
[91] Geft D, Schwartzenberg S, George J. Circulating endothelial progenitor cells in cardiovascular disorders. Expert Rev Cardiovasc Ther, 2008,6(8):1115-1121.
[92] Thum T, Fraccarollo D, Galuppo P, Tsikas D, Frantz S, Ertl G, Bauersachs J. Bone marrow molecular alterationsafter myocardial infarction: Impact on endothelial progenitor cells. Cardiovasc Res, 2006,70:50-60.
[93] Zheng X, Hu SJ . Effects of simvastatin on cardiac performance and expression of sarcoplasmic reticular calcium regulatory proteins in rat heart. Acta Pharmacol Sin, 2005,26:696-704.
[94] Yao L, Chen GP, Lu X, Zheng LR, Mou Y, Hu SJ. Effects of atorvastatin on calcium-regulating proteins: a possible mechanism to repair cardiac dysfunction in spontaneously hypertensive rats. Basic Res Cardiol, 2008 Oct 3. [Epub ahead of print].
[95] Yano M, Ikeda Y, Matsuzaki M. Altered intracellular Ca~(2+) handling in heart failure. J Clin Invest, 2005,115(3):556-564.
[96] Hagemann D, Xiao RP. Dual site phospholamban phosphorylation and its physiological relevance in the heart. Trends Cardiovasc Med, 2002,1 2(2):51-56.
[97] Sande JB, Sjaastad I, Hoen IB, B(?)kenes J, T(?)nnessen T, Holt E, Lunde PK, Christensen G. Reduced level of serine (16) phosphorylated phospholamban in the failing rat myocardium: a major contributor to reduced SERCA2 activity.Cardiovasc Res, 2002,53:382-391.
[98] Nagayama T, Hsu S, Zhang M, Koitabashi N, Bedja D, Gabrielson KL, Takimoto E, Kass DA. Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J Am Coll Cardiol, 2009,53(2):207-215.
[99] Zhang Q, Scholz PM, He Y, Tse J, Weiss HR. Cyclic GMP signaling and regulation of SERCA activity during cardiac myocyte contraction. Cell Calcium, 2005,37(3):259-266.
[100] Colyer J. Phosphorylation states of phospholamban. Ann N Y Acad Sci, 1998, 853:79-91.
[101] Rodr(?)guez-Calvo R, Barroso E, Serrano L, Coll T, S(?)nchez RM, Merlos M, Palomer X, Laguna JC, V(?)zquez-Carrera M. Atorvastatin prevents carbohydrate response element binding protein activation in the fructose-fed rat by activating protein kinase A. Hepatology, 2009,49(1): 106-115.
[102] Fuse M, Tanaka T, Shibata T, Yoshida T, Noguchi Y, Misawa N, Yasuda T, Saito Y, Kohn LD, Tatsuno I. Regulation of geranylgeranyl pyrophosphate synthase in the proliferation of rat FRTL-5 cells: involvement of both cAMP-PKA and PI3-AKT pathways. Biochem Biophys Res Commun, 2004,315(4):1147-1153.
[103] Braz JC, Gregory K, Pathak A, Zhao W, Sahin B, Klevitsky R, Kimball TF, Lorenz JN, Nairn AC, Liggett SB, Bodi I, Wang S, Schwartz A, Lakatta EG,DePaoli-Roach AA, Robbins J, Hewett TE, Bibb JA, Westfall MV, Kranias EG,Molkentin JD PKC-α regulates cardiac contractility and propensity toward heart failure. Nat Med, 2004,10:248-254.
[104] Carr AN, Schmidt AG, Suzuki Y, del Monte F, Sato Y, Lanner C, Breeden K, Jing SL, Allen PB, Greengard P, Yatani A, Hoit BD, Grupp IL, Hajjar RJ,DePaoli-Roach AA, Kranias EG Type 1 Phosphatase, a Negative Regulator of Cardiac Function. Moll Cell Biol, 2002,22:4124-4135.
[105] Gupta RC, Mishra S, Rastogi S, Imai M, Habib O, Sabbah HN Cardiac SR-coupled PP1 activity and expression are increased and inhibitor 1 protein expression is decreased in failing hearts. Am J Physiol Heart Circ Physiol, 2003,285:H2373-H2381.
[106] Paumelle R, Blanquart C, Briand O, Barbier O, Duhem C, Woerly G, Percevault F,Fruchart JC, Dombrowicz D, Glineur C, Staels B. Acute antiinflammatory properties of statins involve peroxisome proliferator-activated receptor-α via inhibition of the protein kinase C signaling pathway. Circ Res, 2006,98:361-369.
[107] Yasunari K, Maeda K, Minami M, Yoshikawa J. HMG-CoA reductase inhibitors prevent migration of human coronary smooth muscle cells through suppression of increase in oxidative stress. Arterioscler Thromb Vasc Biol, 2001,21(6):937-942.
[108] Wollert KC, Yurukova S, Kilic A, Begrow F, Fiedler B, Gambaryan S, Walter U, Lohmann SM, Kuhn M. Increased effects of C-type natriuretic peptide on contractility and calcium regulation in murine hearts overexpressing cyclic GMP-dependent protein kinaseⅠ. Br J Pharmacol, 2003,140(7):1227-1236.
[109] Zhang Q, Scholz PM, Pilzak A, Su J, Weiss HR. Role of phospholamban in cyclic GMP mediated signaling in cardiac myocytes. Cell Physiol Biochem, 2007,20(l-4):157-166.
[110] Su J, Scholz PM, Weiss HR. Differential effects of cGMP produced by soluble and particulate guanylyl cyclase on mouse ventricular myocytes. Exp Biol Med (Maywood), 2005,30(4):242-250.
[111] Chen JC, Huang KC, Lin WW. HMG-CoA reductase inhibitors upregulate heme oxygenase-1 expression in murine RAW264.7 macrophages via ERK, p38 MAPK and protein kinase G pathways. Cell Signal, 2006,18(1):32-39.
[112] Clerk A, Bogoyevitch MA, Fuller SJ, Lazou A, Parker PJ, Sugden PH. Expression of protein kinase C isoforms during cardiac ventricular development. Am J Physiol, 1995,269(3 Pt 2):H1087- H1097.
[113] Rybin VO, Steinberg SF. Protein kinase C isoform expression and regulation in the developing rat heart. Circ Res, 1994,74(2):299-309.
[114] Porter MJ, Heidkamp MC, Scully BT, Patel N, Martin JL, Samarel AM.Isoenzyme-selective regulation of SERCA2 gene expression by protein kin ase C in neonatal rat ventricular myocytes. Am J Physiol Cell Physiol, 2003,285:C39-C47.
[115] Tanaka K, Honda M, Takabatake T. Anti-apoptotic effect of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, on cardiac myocytes through protein kinase C activation. Clin Exp Pharmacol Physiol, 2004,31:360-364.
[116] Khan SG, Saxena R, Bickers DR, Mukhtar H, Agarwal R. Inhibition of ras p21 membrane localization and modulation of protein kinase C isozyme expression during regression of chemical carcinogen-induced murine skin tumors by lovastatin. Mol Carcinog, 1995,12(4):205-212.
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