肾上腺髓质素2在原发性高血压发病中的意义
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摘要
肾上腺髓质素2(adrenomedullin-2，ADM2)／垂体中叶素(intermedin，IMD)是一个降钙素和降钙素基因相关肽(calcitonin gene-related peptide，CGRP)家族的新成员。由于二者在核苷酸和氨基酸序列上完全相同，认为二者为同一物质(以下简称IMD／ADM2)。本研究采用细胞生物学及分子生物学手段，对IMD／ADM2在原发性高血压发生发展过程的作用和病理生理意义进行研究，共分为以下三个部分：
一、自发性高血压大鼠IMD／ADM2血浆含量，组织水平，受体变异，基因表达的相关研究
目的：观察SHR IMD／ADM2血浆含量和组织水平的升降，受体和基因表达的调节变化与SHR血压和心功能的相互关系。方法：8只11周龄的雄性SHR为实验组，8只同龄的雄性WKY为对照组。主要采用放射免疫分析的方法测定血浆和组织中ADM、IMD／ADM2含量；RT-PCR方法测定组织IMD／ADM2、ADM和IMD／ADM2的受体CRLR和受体活性修饰蛋白RAMPs的mRNA含量；Western blot方法测定组织中IMD／ADM2受体-CRLR和RAMPs的蛋白含量；心室导管的方法测定血压和心功能。结果：1．SHR组大鼠在血浆、心肌和主动脉中IMD／ADM2的含量分别高于WKY组大鼠的血浆、心肌和主动脉中的含量(P＜0.01)。2．SHR组大鼠在心肌和主动脉中IMD，ADM，CRLR和RAMPs mRNA水平显著提高(P＜0.01)。3．SHR组的IMD／ADM2血浆含量和收缩压呈显著负相关(P＜0.05)。SHR组的IMD／ADM2血浆含量与其心肌和主动脉的受体系统CRLR、RAMP1、RAMP2、RAMP3 mRNA水平显著相关。结论：IMD／ADM2在SHR的血浆及组织内含量较WKY显著升高，而且这种变化与血压和心脏功能的改变以及受体的调节存在着显著的相关性。提示，IMD／ADM2在原发性高血压发生发展的过程中可能具有重要病理生理意义。
二、采用微量渗透泵给予IMD／ADM2对SHR血压和心功能的影响和作用机制研究
目的：研究IMD／ADM2对自发性高血压大鼠(SHR)血压和心功能的影响及可能机制。方法：采用皮下埋入微量渗透泵给予IMD／ADM2的方法，把11周龄雄性SHR分三组(n=8)；IMD组，ADM组和SHR对照组。分别给药埋泵两周后，用RT-PCR测定各组大鼠心肌及主动脉的CRLR和RAMPs以及脑钠素(BNP)、心钠素(ANP)的mRNA表达情况。结果：1．同SHR组相比较，IMD组收缩压，±LV dp／dtmax，LVSP，心率分别均显著降低(P＜0.01)。2．心肌中，IMD组ANPmRNA表达较SHR组显著增高(P＜0.01)，BNPmRNA表达也显著升高(P＜0.01)。3．受体研究显示：心肌中，IMD组与SHR组比较，CRLR mRNA的表达上升22％(P＜0.05)。主动脉中，IMD组的RAMP1，2，3和CRLR均显著下降(P＜0.05)。结论：1．采用微量渗透泵给予IMD／ADM2可以显著降低SHR的血压并改善其心功能。2．IMD／ADM2可以通过调节体内ANP和BNP水平共同产生降压和心功能保护作用。3．给予外源性的IMD／ADM2可以对其受体系统RAMPs和CRLR的表达产生影响，。
三、IMD／ADM2心血管作用的信号传导研究
目的：探讨IMD／ADM2对第二信使cAMP在SHR血管分泌的调节作用。方法：8只11周龄的雄性SHR为实验组，8只同龄的雄性WKY为对照组。断头处死后，将组织切成薄片，依次加入不同剂量的IMD，IMD+ADM_(22-52)，IMD+CGRP_(8-37)和ADM。孵育后，煮沸，匀浆。采用放射免疫方法测定细胞内cAMP的水平。结果1．SHR组大鼠在心肌离体孵育后给予不同剂量的IMD后cAMP水平较与WKY组大鼠显著降低(P＜0.05)，而在主动脉则显著升高(P＜0.05) 2．在SHR组中，主动脉在离体孵育给予ADM_(22-52)后cAMP含量增高(P＜0.01)，而给予CGRP_(8-37)后心肌和血管cAMP均含量降低，但是这种变化均无统计学意义。结论1．IMD／ADM2可以显著升高SHR血管产生cAMP。而且，升高幅度显著大于WKY，这可能是SHR对IMD／ADM2敏感性的改变所至。2．CGRP家族受体的阻断剂均不能单独阻断IMD／ADM2刺激SHR心血管组织产生cAMP的作用。提示高血压大鼠体内，IMD／ADM2的血管舒张作用仍然可以非选择地通过CGRP1、ADM1和ADM2受体发挥作用的。
Adrenomedullin-2(ADM2) and intermedin(IMD) are new familial members of calcitionin and calcitonin gene-related peptide (CGRP). They are regarded as identical substance because of their same nucleotide and amino acid sequence (intermedin/ adrenomedullin 2, IMD/ADM2). A study applying cytobiology and molecular biology methods was designed to explore the physiological and pathological significance of IMD/ADM2 in the occurrence and development process of essential hypertension. This study was divided into three parts.
1. Study about IMD/ADM2 for levels in blood plasma and tissues, recipient variation and genetic expression in SHR
Objective: To observe changes of IMD/ADM2 in the levels of blood plasma and tissues, relationship between regulations of recipient or genetic expression and blood pressure, heart function. Methods: There were 8 male SHR of 11 weeks old in experiment group, 8 male WKY of the same age in control group. The protein amount of of ADM and IMD/ADM2 in blood plasma and tissue were obtained by radioimmunoassay. mRNA expression of CRLR and RAMPs were measured by RT-PCR method. The protein levels of CRLR and RAMPs were measured by Western blot. Data of blood pressure and heart function were obtained with cardiac catheterization. Results: 1. In SHR group, levels of IMD in blood plasma, myocardium and aorta were higher than that in WKY group (P<0.01). 2. mRNA levels of IMD/ADM2, ADM, CRLR and RAMP1, RAMP2, RAMP3 increased respectively in both myocardium and aorta in SHR (P<0.01). 3. In SHR group, IMD/ADM2 of blood plasma had significant negative correlation with SBP (P<0.05). In SHR group, levels of IMD/ADM2 in blood plasma had correlation with mRNA levels of recipient system including CRLR, RAMP1, RAMP2, RAMP3. Conclusions: These results suggest that IMD/ADM2 may have important physiological and pathological significance during the occurrence and
development process of essential hypertension.
2. Effect on blood pressure/heart function of SHR by applying mini-osmotic pump with IMD/ADM2 and possible mechanism
Objective: To study the effect of IMD/ADM2 on SHR blood pressure/heart function and possible mechanism. Methods: Applying mini-osmotic pump implanted subcutaneouly, after two weeks, the levels of cAMP were measured by radioimmunoassay. Data including CRLR and RAMPs in left ventricle cardiac muscle and aorta, mRNA expression of BNP and atrial natriuretic peptide ANP were measured by semiquantitative RT-PCR method. Results: 1. Compared with that in SHR group, SBP, ±LV dp/dtmax, LVSP and heart rates in IMD group were decreased significantly (P<0.01). 2. The levels of ANP mRNA and BNP mRNA in cardiac muscle were higher in IMD group compared with that in WKY and SHR groups (P<0.01). 3. Results in acceptor study showed that CRLR mRNA expression increased by 22% in IMD group than that in SHR group (P<0.05). In aorta, expression of RAMPs and CRLR were significantly lower in IMD (P<0.05). Conclusions: 1. IMD/ADM2 could decrease SHR blood pressure significantly and improve heart function. 2. IMD/ADM2 can work with some other cardiovascular active factors like ANP and BNP in body, which will lead to depressurization and heart function protection. 3. Eectogenic IMD/ADM2 can affect acceptor expression of RAMPs and CRLR in their acceptor system.
3. Signal conduction effect of IMD/ADM2 on blood vessels
Objective: To explore how IMD/ADM2 affects the second messenger cAMP to adjust blood vessel secretion in SHR. Methods: SHR and WKY were executed by decapitation, then aorta blood vessel in chest and abdomen were taken out and sliced.Different doses of IMD, IMD+ADM_(22-52), IMD+CGRP_(8-37) and ADM were added into sample one by one. After incubation, sample was boiled and homogenated. Level of cAMP in cells was measured by radioimmunoassay methods. Results: 1. After incubation and given different doses of IMD, levels of cAMP in ex vivo cardiac muscle in SHR group were decreased compared with that in WKY group (P<0.05) and increased in aorta (P<0.05).2. In SHR group,
levels of cAMP were increased after ADM_(22-52) were added into ex vivo aorta (P<0.01), and in cardiac muscle, decreased after CGRP_(8-37) were added into these samples. But there was no statistics significance for these changes. Conclusions: 1. IMD/ADM2 can induce blood vessel in SHR to produce cAMP similar with the way in normal rat. On the other hand, secretory volume of cAMP is higher significantly than that in WKY group. The sensitivity to change in SHR for IMD maybe is the reason of that. 2. No matter was it ADM_(22-52) or CGRP_(8-37), neither of them could block alone IMD/ADM2 to stimulate cardiovascular tissue in SHR producing cAMP. These results suggested that IMD/ADM2 could produce a marked effect of vasodilatation through acceptor of CGRP1, ADM1 and ADM2 no-selectively.
一、自发性高血压大鼠IMD／ADM2血浆含量，组织水平，受体变异，基因表达的相关研究
目的：观察SHR IMD／ADM2血浆含量和组织水平的升降，受体和基因表达的调节变化与SHR血压和心功能的相互关系。方法：8只11周龄的雄性SHR为实验组，8只同龄的雄性WKY为对照组。主要采用放射免疫分析的方法测定血浆和组织中ADM、IMD／ADM2含量；RT-PCR方法测定组织IMD／ADM2、ADM和IMD／ADM2的受体CRLR和受体活性修饰蛋白RAMPs的mRNA含量；Western blot方法测定组织中IMD／ADM2受体-CRLR和RAMPs的蛋白含量；心室导管的方法测定血压和心功能。结果：1．SHR组大鼠在血浆、心肌和主动脉中IMD／ADM2的含量分别高于WKY组大鼠的血浆、心肌和主动脉中的含量(P＜0.01)。2．SHR组大鼠在心肌和主动脉中IMD，ADM，CRLR和RAMPs mRNA水平显著提高(P＜0.01)。3．SHR组的IMD／ADM2血浆含量和收缩压呈显著负相关(P＜0.05)。SHR组的IMD／ADM2血浆含量与其心肌和主动脉的受体系统CRLR、RAMP1、RAMP2、RAMP3 mRNA水平显著相关。结论：IMD／ADM2在SHR的血浆及组织内含量较WKY显著升高，而且这种变化与血压和心脏功能的改变以及受体的调节存在着显著的相关性。提示，IMD／ADM2在原发性高血压发生发展的过程中可能具有重要病理生理意义。
二、采用微量渗透泵给予IMD／ADM2对SHR血压和心功能的影响和作用机制研究
目的：研究IMD／ADM2对自发性高血压大鼠(SHR)血压和心功能的影响及可能机制。方法：采用皮下埋入微量渗透泵给予IMD／ADM2的方法，把11周龄雄性SHR分三组(n=8)；IMD组，ADM组和SHR对照组。分别给药埋泵两周后，用RT-PCR测定各组大鼠心肌及主动脉的CRLR和RAMPs以及脑钠素(BNP)、心钠素(ANP)的mRNA表达情况。结果：1．同SHR组相比较，IMD组收缩压，±LV dp／dtmax，LVSP，心率分别均显著降低(P＜0.01)。2．心肌中，IMD组ANPmRNA表达较SHR组显著增高(P＜0.01)，BNPmRNA表达也显著升高(P＜0.01)。3．受体研究显示：心肌中，IMD组与SHR组比较，CRLR mRNA的表达上升22％(P＜0.05)。主动脉中，IMD组的RAMP1，2，3和CRLR均显著下降(P＜0.05)。结论：1．采用微量渗透泵给予IMD／ADM2可以显著降低SHR的血压并改善其心功能。2．IMD／ADM2可以通过调节体内ANP和BNP水平共同产生降压和心功能保护作用。3．给予外源性的IMD／ADM2可以对其受体系统RAMPs和CRLR的表达产生影响，。
三、IMD／ADM2心血管作用的信号传导研究
目的：探讨IMD／ADM2对第二信使cAMP在SHR血管分泌的调节作用。方法：8只11周龄的雄性SHR为实验组，8只同龄的雄性WKY为对照组。断头处死后，将组织切成薄片，依次加入不同剂量的IMD，IMD+ADM_(22-52)，IMD+CGRP_(8-37)和ADM。孵育后，煮沸，匀浆。采用放射免疫方法测定细胞内cAMP的水平。结果1．SHR组大鼠在心肌离体孵育后给予不同剂量的IMD后cAMP水平较与WKY组大鼠显著降低(P＜0.05)，而在主动脉则显著升高(P＜0.05) 2．在SHR组中，主动脉在离体孵育给予ADM_(22-52)后cAMP含量增高(P＜0.01)，而给予CGRP_(8-37)后心肌和血管cAMP均含量降低，但是这种变化均无统计学意义。结论1．IMD／ADM2可以显著升高SHR血管产生cAMP。而且，升高幅度显著大于WKY，这可能是SHR对IMD／ADM2敏感性的改变所至。2．CGRP家族受体的阻断剂均不能单独阻断IMD／ADM2刺激SHR心血管组织产生cAMP的作用。提示高血压大鼠体内，IMD／ADM2的血管舒张作用仍然可以非选择地通过CGRP1、ADM1和ADM2受体发挥作用的。
Adrenomedullin-2(ADM2) and intermedin(IMD) are new familial members of calcitionin and calcitonin gene-related peptide (CGRP). They are regarded as identical substance because of their same nucleotide and amino acid sequence (intermedin/ adrenomedullin 2, IMD/ADM2). A study applying cytobiology and molecular biology methods was designed to explore the physiological and pathological significance of IMD/ADM2 in the occurrence and development process of essential hypertension. This study was divided into three parts.
1. Study about IMD/ADM2 for levels in blood plasma and tissues, recipient variation and genetic expression in SHR
Objective: To observe changes of IMD/ADM2 in the levels of blood plasma and tissues, relationship between regulations of recipient or genetic expression and blood pressure, heart function. Methods: There were 8 male SHR of 11 weeks old in experiment group, 8 male WKY of the same age in control group. The protein amount of of ADM and IMD/ADM2 in blood plasma and tissue were obtained by radioimmunoassay. mRNA expression of CRLR and RAMPs were measured by RT-PCR method. The protein levels of CRLR and RAMPs were measured by Western blot. Data of blood pressure and heart function were obtained with cardiac catheterization. Results: 1. In SHR group, levels of IMD in blood plasma, myocardium and aorta were higher than that in WKY group (P<0.01). 2. mRNA levels of IMD/ADM2, ADM, CRLR and RAMP1, RAMP2, RAMP3 increased respectively in both myocardium and aorta in SHR (P<0.01). 3. In SHR group, IMD/ADM2 of blood plasma had significant negative correlation with SBP (P<0.05). In SHR group, levels of IMD/ADM2 in blood plasma had correlation with mRNA levels of recipient system including CRLR, RAMP1, RAMP2, RAMP3. Conclusions: These results suggest that IMD/ADM2 may have important physiological and pathological significance during the occurrence and
development process of essential hypertension.
2. Effect on blood pressure/heart function of SHR by applying mini-osmotic pump with IMD/ADM2 and possible mechanism
Objective: To study the effect of IMD/ADM2 on SHR blood pressure/heart function and possible mechanism. Methods: Applying mini-osmotic pump implanted subcutaneouly, after two weeks, the levels of cAMP were measured by radioimmunoassay. Data including CRLR and RAMPs in left ventricle cardiac muscle and aorta, mRNA expression of BNP and atrial natriuretic peptide ANP were measured by semiquantitative RT-PCR method. Results: 1. Compared with that in SHR group, SBP, ±LV dp/dtmax, LVSP and heart rates in IMD group were decreased significantly (P<0.01). 2. The levels of ANP mRNA and BNP mRNA in cardiac muscle were higher in IMD group compared with that in WKY and SHR groups (P<0.01). 3. Results in acceptor study showed that CRLR mRNA expression increased by 22% in IMD group than that in SHR group (P<0.05). In aorta, expression of RAMPs and CRLR were significantly lower in IMD (P<0.05). Conclusions: 1. IMD/ADM2 could decrease SHR blood pressure significantly and improve heart function. 2. IMD/ADM2 can work with some other cardiovascular active factors like ANP and BNP in body, which will lead to depressurization and heart function protection. 3. Eectogenic IMD/ADM2 can affect acceptor expression of RAMPs and CRLR in their acceptor system.
3. Signal conduction effect of IMD/ADM2 on blood vessels
Objective: To explore how IMD/ADM2 affects the second messenger cAMP to adjust blood vessel secretion in SHR. Methods: SHR and WKY were executed by decapitation, then aorta blood vessel in chest and abdomen were taken out and sliced.Different doses of IMD, IMD+ADM_(22-52), IMD+CGRP_(8-37) and ADM were added into sample one by one. After incubation, sample was boiled and homogenated. Level of cAMP in cells was measured by radioimmunoassay methods. Results: 1. After incubation and given different doses of IMD, levels of cAMP in ex vivo cardiac muscle in SHR group were decreased compared with that in WKY group (P<0.05) and increased in aorta (P<0.05).2. In SHR group,
levels of cAMP were increased after ADM_(22-52) were added into ex vivo aorta (P<0.01), and in cardiac muscle, decreased after CGRP_(8-37) were added into these samples. But there was no statistics significance for these changes. Conclusions: 1. IMD/ADM2 can induce blood vessel in SHR to produce cAMP similar with the way in normal rat. On the other hand, secretory volume of cAMP is higher significantly than that in WKY group. The sensitivity to change in SHR for IMD maybe is the reason of that. 2. No matter was it ADM_(22-52) or CGRP_(8-37), neither of them could block alone IMD/ADM2 to stimulate cardiovascular tissue in SHR producing cAMP. These results suggested that IMD/ADM2 could produce a marked effect of vasodilatation through acceptor of CGRP1, ADM1 and ADM2 no-selectively.
引文
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[1] 罗碧辉，曾昭华，易家骥，等．培哚普利对盐敏感性高血压大鼠心脏形态及其功能的影响．中国心血管杂志．2004，6：393-396．
[2] Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976, 72:248-254.
[3] Kitamura K, Kato J, Kawamoto M, et al. The intermediate form of glycine-extended adrenomedullin is the major circulating molecular form in human plasma. Biochem Biophys Res Commun. 1998, 244(2):551-555.
[4] Kobayashi H, Yamamoto R, Kitamura K, et al. Cyclic AMP-dependent synthesis and release of adrenomedullin and proadrenomedullin N-terminal 20 peptide in cultured bovine adrenal chromaffin cells. Eur J Biochem. 1999, 263(3):702-708.
[5] F．M 奥斯伯，R．布伦特，R．E．金斯顿，等．精编分子生物学实验指南．颜子颖， 王海林译．科学出版社，1998，第一版：89-115．
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[7] Takei Y, Inoue K, Ogoshi M, et al. Identification of novel adrenomedullin in mammals: a potent cardiovascular and renal regulator. FEBS Lett. 2004, 556(1-3):53-58.
[8] Roh J, Chang CL, Bhalla A, et al. Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes. J Biol Chem. 2004, 279(8):7264-7274.
[9] Zhao Y, Bell D, Smith LR, et al. Differential expression of components of the cardiomyocyte adrenomedullin/intermedin receptor system following blood pressure reduction in nitric oxide-deficient hypertension. J Pharmacol Exp Ther. 2006, 316(3):1269-1281.
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[13] 齐永芬，唐朝枢．降钙素基因相关肽家族的受体活性修饰蛋白．生理科学进展．2001，22：251-253．
[14] McLatchie LM, Fraser NJ, Main MJ, et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature. 1998, 393(6683):333-339.
[15]Thota C, Gangula PR, Dong YL, et al. Changes in the expression of calcitonin receptor-like receptor, receptor activity-modifying protein (RAMP) 1, RAMP2, and RAMP3 in rat uterus during pregnancy, labor, and by steroid hormone treatments. Biol Reprod. 2003, 69(4):1432-1437.
[16] Qi YF, Shi YR, Bu DF, et al. Changes of adrenomedullin and receptor activity modifying protein 2 (RAMP2) in myocardium and aorta in rats with isoproterenol-induced myocardial ischemia. Peptides. 2003,24(3):463-468.
[17]Totsune K, Takahashi K, Mackenzie HS, et al. Increased gene expression of adrenomedullin and adrenomedullin-receptor complexes, receptor-activity modifying protein (RAMP)2 and calcitonin-receptor-like receptor (CRLR) in the hearts of rats with congestive heart failure. Clin Sci (Lond). 2000, 99(6):541-546.
[18]Hinson JP, Kapas S, Smith DM. Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev. 2000, 21(2): 138-167.
[19] Chang CL, Roh J, Hsu SY. Intermedin, a novel calcitonin family peptide that exists in teleosts as well as in mammals: a comparison with other calcitonin/intermedin family peptides in vertebrates. Peptides. 2004,25(10):1633-1642.
[20]Kuwasako K, Kitamura K, Onitsuka H, et al. Rat RAMP domains involved in adrenomedullin binding specificity. FEBS Lett. 2007, 519(1-3):113-116.
[21] [21] Frayon S, Cueille C, Gnidehou S, et al. Dexamethasone increases RAMP1 and CRLR mRNA expressions in human vascular smooth muscle cells. Biochem Biophys Res Commun. 2000,270(3): 1063-1067.
[22]Nagae T, Mukoyama M, Sugawara A, et al. Rat receptor-activity-modifying proteins (RAMPs) for adrenomedullin/CGRP receptor: cloning and upregulation in obstructive nephropathy. Biochem Biophys Res Commun.2000, 270(1):89-93.
[23] Caron KM, Smithies O.Extreme hydrops fetalis and cardiovascular abnormalities in mice lacking a functional Adrenomedullin gene. Proc Natl Acad Sci U S A. 2001, 98(2):615-619.
[24] 贾月霞，李桂忠，杨靖辉，等．急性心力衰竭大鼠心肌intermedin受体的变化．宁夏医学院学报．2005，27：337-339。
[25] Zhao Y, Bell D, Smith LR, et al. Differential expression of components of the cardiomyocyte adrenomedullin/intermedin receptor system following blood pressure reduction in nitric oxide-deficient hypertension. J Pharmacol Exp Ther. 2006, 316(3): 1269-1281.
[26] Mishima K, Kato J, Kuwasako K, et al. Effects of endothelin on adrenomedullin secretion and expression of adrenomedullin receptors in rat cardiomyocytes. Biochem Biophys Res Commun. 2001,287(1):264-269.
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