靶向高密度脂蛋白的动脉粥样硬化防治研究:从升高水平到改善功能
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摘要
动脉粥样硬化(atherosclerosis,AS)是一种血管炎症性病变,是心肌梗死和脑卒中的重要原因。预计到2020年,AS将成为世界范围内首要致死病因。AS的防治策略研究一直是心血管领域的研究重点,而高密度脂蛋白(high density lipoprotein,HDL)因具有良好的抗AS作用一直被认为是药物开发的靶点。本综述将重点讨论目前增加血浆HDL水平和改善其功能的药物研发策略以及它们的可行性和局限性,同时就HDL新药物研究加以展望。
Atherosclerosis(AS) is the major etiology for myocardial infarction and stroke, which is projected to be the greatest killer by 2020. Strategies to prevent AS have been intensively studied in recent years. High density lipoprotein(HDL) is considered one of the most important therapeutic targets as it functions in a critical manner in the pathogenesis of AS and negatively correlates with incidence. In this review, therefore, we summarize the progress of drug development targeting HDL, focusing on feasibility and limitations. Moreover, we provide our perspectives related to challenges and opportunites related to AS and mediation and/or modulation of HDL.
Atherosclerosis(AS) is the major etiology for myocardial infarction and stroke, which is projected to be the greatest killer by 2020. Strategies to prevent AS have been intensively studied in recent years. High density lipoprotein(HDL) is considered one of the most important therapeutic targets as it functions in a critical manner in the pathogenesis of AS and negatively correlates with incidence. In this review, therefore, we summarize the progress of drug development targeting HDL, focusing on feasibility and limitations. Moreover, we provide our perspectives related to challenges and opportunites related to AS and mediation and/or modulation of HDL.
引文
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[16]Goedeke L,Rotllan N,Canfran-Duque A,et al.MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels[J].Nat Med,2015,21(11):1280-1289.
[17]Najafi-Shoushtari SH,Kristo F,Li Y,et al.MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis [J].Science,2010,328(5985):1566-1569.
[18]Rayner KJ,Esau CC,Hussain FN,et al.Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides[J].Nature,2011,478(7369):404-407.
[19]Osei-Hwedieh DO,Amar M,Sviridov D,et al.Apolipoprotein mimetic peptides:Mechanisms of action as anti-atherogenic agents[J].Pharmacol Ther,2011,130(1):83-91.
[20]Navab M,Anantharamaiah G M,Hama S,et al.Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol[J].Circulation,2002,105(3):290-292.
[21]Chattopadhyay A,Navab M,Hough G,et al.A novel approach to oral apoA-I mimetic therapy[J].J Lipid Res,2013,54(4):995-1010.
[22]Bloedon LT,Dunbar R,Duffy D,et al.Safety,pharmacokinetics,and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients[J].J Lipid Res,2008,49(6):1344-1352.
[23]Krause BR,Remaley AT.Reconstituted HDL for the acute treatment of acute coronary syndrome [J].Curr Opin Lipidol,2013,24(6):480- 486.
[24]Kallend DG,Reijers JA,Bellibas SE,et al.A single infusion of MDCO-216 (ApoA-1 Milano/POPC) increases ABCA1-mediated cholesterol efflux and pre-beta 1 HDL in healthy volunteers and patients with stable coronary artery disease[J].Eur Heart J Cardiovasc Pharmacother,2016,2(1):23-29.
[25]Karalis I,Jukema JW.HDL Mimetics Infusion and Regression of Atherosclerosis:Is It Still Considered a Valid Therapeutic Option?[J].Curr Cardiol Rep,2018,20(8):66.
[26]Tardif JC,Ballantyne CM,Barter P,et al.Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes:a randomized trial [J].Eur Heart J,2014,35(46):3277-3286.
[27]Dobesh PP,Beavers CJ,Herring HR,et al.Key articles and guidelines in the management of acute coronary syndrome and in percutaneous coronary intervention:2012 update[J].Pharmacotherapy,2012,32(12):e348-386.
[28]Tardif JC,Gregoire J,L’Allier PL,et al.Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis:a randomized controlled trial[J].JAMA,2007,297(15):1675-1682.
[29]Shaw JA,Bobik A,Murphy A,et al.Infusion of reconstituted high-density lipoprotein leads to acute changes in human atherosclerotic plaque[J].Circ Res,2008,103(10):1084-1091.
[30]Ossoli A,Simonelli S,Vitali C,et al.Role of LCAT in Atherosclerosis[J].J Atheroscler Thromb,2016,23(2):119-127.
[31]Rousset X,Shamburek R,Vaisman B,et al.Lecithin cholesterol acyltransferase:an anti- or pro-atherogenic factor?[J].Curr Atheroscler Rep,2011,13(3):249-256.
[32]Dullaart RP,Tietge UJ,Kwakernaak AJ,et al.Alterations in plasma lecithin:cholesterol acyltransferase and myeloperoxidase in acute myocardial infarction:implications for cardiac outcome[J].Atherosclerosis,2014,234(1):185-192.
[33]Tani S,Takahashi A,Nagao K,et al.Association of lecithin-cholesterol acyltransferase activity measured as a serum cholesterol esterification rate and low-density lipoprotein heterogeneity with cardiovascular risk:a cross-sectional study[J].Heart Vessels,2016,31(6):831-840.
[34]Calabresi L,Baldassarre D,Simonelli S,et al.Plasma lecithin:cholesterol acyltransferase and carotid intima-media thickness in European individuals at high cardiovascular risk[J].J Lipid Res,2011,52(8):1569-1574.
[35]Zanoni P,Khetarpal SA,Larach DB,et al.Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease[J].Science,2016,351(6278):1166-1171.
[36]Cui GH,Chen WQ,Shen ZY.Urolithin A shows anti-atherosclerotic activity via activation of class B scavenger receptor and activation of Nef2 signaling pathway[J].Pharmacol Rep,2018,70(3):519-524.
[37]Ronsein GE,Heinecke JW.Time to ditch HDL-C as a measure of HDL function?[J].Curr Opin Lipidol,2017,28(5):414-418.
[2] Parhofer KG.Increasing HDL-cholesterol and prevention of atherosclerosis:A critical perspective[J].Atheroscler Suppl,2015,18:109-111.
[3] Tong X,Peng H,Liu D,et al.High-density lipoprotein of patients with type 2 diabetes mellitus upregulates cyclooxgenase-2 expression and prostacyclin I-2 release in endothelial cells:relationship with HDL-associated sphingosine-1-phosphate[J].Cardiovasc Diabetol,2013,12:27.doi:10.1186/1475-2840-12-27.
[4] Munoz-Vega M,Masso F,Paez A,et al.HDL-Mediated Lipid Influx to Endothelial Cells Contributes to Regulating Intercellular Adhesion Molecule (ICAM)-1 Expression and eNOS Phosphorylation[J].Int J Mol Sci,2018,19(11).doi:10.3390/ijms19113394.
[5] Li H,Tang H,Fang D Z,et al.The effect of high density lipoprotein and oxidized high density lipoprotein on some secretive functions of endothelial cells[J].Sichuan Da Xue Xue Bao Yi Xue Ban,2005,36(5):637-640.
[6] Woudberg NJ,Mendham AE,Katz AA,et al.Exercise intervention alters HDL subclass distribution and function in obese women[J].Lipids Health Dis,2018,17(1):232.
[7] Birjmohun RS,Hutten BA,Kastelein JJ,et al.Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds:a meta-analysis of randomized controlled trials[J].J Am Coll Cardiol,2005,45(2):185-197.
[8] Investigators AH,Boden WE,Probstfield JL,et al.Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy[J].N Engl J Med,2011,365(24):2255-2267.
[9]HPS2-THRIVE Collaborative Group.HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant:trial design,pre-specified muscle and liver outcomes,and reasons for stopping study treatment [J].Eur Heart J,2013,34(17):1279-1291.
[10]Williams SA,Murthy AC,DeLisle RK,et al.Improving Assessment of Drug Safety Through Proteomics:Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib[J].Circulation,2018,137(10):999-1010.
[11]Schwartz GG,Olsson AG,Abt M,et al.Effects of dalcetrapib in patients with a recent acute coronary syndrome[J].N Engl J Med,2012,367(22):2089-2099.
[12]Lincoff AM,Nicholls SJ,Riesmeyer JS,et al.Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease[J].N Engl J Med,2017,376(20):1933-1942.
[13]Barylski M,Toth PP,Nikolic D,et al.Emerging therapies for raising high-density lipoprotein cholesterol (HDL-C) and augmenting HDL particle functionality[J].Best Pract Res Clin Endocrinol Metab,2014,28(3):453-461.
[14]Timmins JM,Lee JY,Boudyguina E,et al.Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I[J].J Clin Invest,2005,115(5):1333-1342.
[15]Aiello RJ,Brees D,Francone OL.ABCA1-deficient mice:insights into the role of monocyte lipid efflux in HDL formation and inflammation[J].Arterioscler Thromb Vasc Biol,2003,23(6):972-980.
[16]Goedeke L,Rotllan N,Canfran-Duque A,et al.MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels[J].Nat Med,2015,21(11):1280-1289.
[17]Najafi-Shoushtari SH,Kristo F,Li Y,et al.MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis [J].Science,2010,328(5985):1566-1569.
[18]Rayner KJ,Esau CC,Hussain FN,et al.Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides[J].Nature,2011,478(7369):404-407.
[19]Osei-Hwedieh DO,Amar M,Sviridov D,et al.Apolipoprotein mimetic peptides:Mechanisms of action as anti-atherogenic agents[J].Pharmacol Ther,2011,130(1):83-91.
[20]Navab M,Anantharamaiah G M,Hama S,et al.Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol[J].Circulation,2002,105(3):290-292.
[21]Chattopadhyay A,Navab M,Hough G,et al.A novel approach to oral apoA-I mimetic therapy[J].J Lipid Res,2013,54(4):995-1010.
[22]Bloedon LT,Dunbar R,Duffy D,et al.Safety,pharmacokinetics,and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients[J].J Lipid Res,2008,49(6):1344-1352.
[23]Krause BR,Remaley AT.Reconstituted HDL for the acute treatment of acute coronary syndrome [J].Curr Opin Lipidol,2013,24(6):480- 486.
[24]Kallend DG,Reijers JA,Bellibas SE,et al.A single infusion of MDCO-216 (ApoA-1 Milano/POPC) increases ABCA1-mediated cholesterol efflux and pre-beta 1 HDL in healthy volunteers and patients with stable coronary artery disease[J].Eur Heart J Cardiovasc Pharmacother,2016,2(1):23-29.
[25]Karalis I,Jukema JW.HDL Mimetics Infusion and Regression of Atherosclerosis:Is It Still Considered a Valid Therapeutic Option?[J].Curr Cardiol Rep,2018,20(8):66.
[26]Tardif JC,Ballantyne CM,Barter P,et al.Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes:a randomized trial [J].Eur Heart J,2014,35(46):3277-3286.
[27]Dobesh PP,Beavers CJ,Herring HR,et al.Key articles and guidelines in the management of acute coronary syndrome and in percutaneous coronary intervention:2012 update[J].Pharmacotherapy,2012,32(12):e348-386.
[28]Tardif JC,Gregoire J,L’Allier PL,et al.Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis:a randomized controlled trial[J].JAMA,2007,297(15):1675-1682.
[29]Shaw JA,Bobik A,Murphy A,et al.Infusion of reconstituted high-density lipoprotein leads to acute changes in human atherosclerotic plaque[J].Circ Res,2008,103(10):1084-1091.
[30]Ossoli A,Simonelli S,Vitali C,et al.Role of LCAT in Atherosclerosis[J].J Atheroscler Thromb,2016,23(2):119-127.
[31]Rousset X,Shamburek R,Vaisman B,et al.Lecithin cholesterol acyltransferase:an anti- or pro-atherogenic factor?[J].Curr Atheroscler Rep,2011,13(3):249-256.
[32]Dullaart RP,Tietge UJ,Kwakernaak AJ,et al.Alterations in plasma lecithin:cholesterol acyltransferase and myeloperoxidase in acute myocardial infarction:implications for cardiac outcome[J].Atherosclerosis,2014,234(1):185-192.
[33]Tani S,Takahashi A,Nagao K,et al.Association of lecithin-cholesterol acyltransferase activity measured as a serum cholesterol esterification rate and low-density lipoprotein heterogeneity with cardiovascular risk:a cross-sectional study[J].Heart Vessels,2016,31(6):831-840.
[34]Calabresi L,Baldassarre D,Simonelli S,et al.Plasma lecithin:cholesterol acyltransferase and carotid intima-media thickness in European individuals at high cardiovascular risk[J].J Lipid Res,2011,52(8):1569-1574.
[35]Zanoni P,Khetarpal SA,Larach DB,et al.Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease[J].Science,2016,351(6278):1166-1171.
[36]Cui GH,Chen WQ,Shen ZY.Urolithin A shows anti-atherosclerotic activity via activation of class B scavenger receptor and activation of Nef2 signaling pathway[J].Pharmacol Rep,2018,70(3):519-524.
[37]Ronsein GE,Heinecke JW.Time to ditch HDL-C as a measure of HDL function?[J].Curr Opin Lipidol,2017,28(5):414-418.