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L-精氨酸一氧化氮途径对病理性心肌肥厚形成的抑制作用及相关机制
杨涛1,张伟2,张雷1*
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(1.河北医科大学组织学与胚胎学教研室，石家庄 050017;2.河北医科大学基础课部药理教研室，石家庄 050091)

摘要:

目的:从在体和离体水平分别探讨L精氨酸对病理性心肌肥厚的影响及相关机制。方法:(1)在体水平:将大鼠分为假手术组、手术组、L精氨酸 (Larginine, LArg) 组和L硝基精氨酸甲酯 (NnitroLarginine methyl ester, LNAME) 组(LArg+LNAME组),利用腹主动脉缩窄制作大鼠模型。检测心肌内蛋白合成总量与心率、血压；比色法检测心肌内一氧化氮（NO）含量、放射免疫法检测心肌ATⅡ含量，RTPCR检测心肌内血管紧张素转换酶（angiotensin converting enzyme, ACE）mRNA的表达水平。(2)离体水平:将原代培养的心肌细胞分为对照组、血管紧张素Ⅱ(Angiotensin Ⅱ，ATⅡ) 处理组、LArg处理组(ATⅡ+LArg)及LNAME处理组(ATⅡ+LArg+LNAME)。RTPCR检测原代培养心肌细胞诱导型一氧化氮合酶 (inducible NO synthase, iNOS)、ATⅡ的1型受体(ATⅡ receptor type 1, ATR1)和2型受体(ATⅡ receptor type 2, ATR2)mRNA的表达水平；Western印迹法检测原代培养心肌细胞iNOS蛋白表达水平。结果:(1)LArg提高了腹主动脉缩窄大鼠心肌内NO含量，降低了心肌ATⅡ含量、心肌蛋白合成总量、左心室质量/体质量比值以及ACE mRNA的表达量；LNAME可消除LArg的上述作用；(2)在离体条件下，与ATⅡ组相比，LArg处理组心肌细胞NO含量、iNOS mRNA及蛋白水平的表达量均有提高，ATR1 mRNA表达水平下降； LNAME处理组与ATⅡ处理组就上述指标相比无显著性差异；各组细胞ATR2 mRNA表达水平无明显差异；(3)多元逐步回归分析显示心肌内蛋白合成总量与血压水平、心率之间均不存在回归关系，而心肌NO和ATⅡ含量则可作为心肌内蛋白合成总量的预测因子；(4)心肌内ATⅡ含量、ACE mRNA表达量及心肌细胞ATR1 mRNA表达量均与NO含量之间存在线形负相关关系。结论:(1)心肌肥厚的形成与心肌内NO、ATⅡ含量密切相关；(2)LArg通过增强心肌iNOS表达，致NO生成增加。NO可减少心肌内ATⅡ生成，并通过调控心肌ACE及ATR1表达来抑制病理性心肌肥厚的形成；(3)ATR2并未参与上述过程。

关键词: L-精氨酸一氧化氮诱导型一氧化氮合酶血管紧张素Ⅱ 心肌肥厚

DOI：10.3724/SP.J.1008.2008.00177

投稿时间：2007-10-17修订日期：2007-11-08

基金项目:

Inhibitory effects of L-arginine nitric oxide pathway on formation of pathological cardiac hypertrophy and the related mechanisms

YANG Tao1,ZHANG Wei2,ZHANG Lei1*

(1.Department of Histology and Embryology, Hebei Medical University, Shijiazhuang 050017, China;2.Department of Pharmacology, School of Basic Medicine,Hebei Medical University, Shijiazhuang 050091)

Abstract:

Objective：To evaluate the in vivo and in vitro effects of Larginine (LArg) on cardiac hypertrophy and the related mechanisms. Methods: (1) In vivo study, rats were divided into shamoperation group, operation group, Larginine (LArg) group, and NnitroLarginine methyl ester (LNAME) group.Coarctation of abdominal aortic artery was performed in rats of the operation group,LArg group and LNAME group. The total protein level in the heart, the heart rate and blood pressure were all determined; cardiac nitric oxide (NO) content was detected by colorimetric method; cardiac ATⅡ content was determined by radioimmunoassay; and the expression of angiotensin converting enzyme (ACE) mRNA was determined by RTPCR. (2) In vitro study, primarily cultured cardiomyocytes were divided into control group, Angiotensin Ⅱ (ATⅡ)treated group, LArg treated group, and LNAME treated group. RTPCR was used to examine the mRNA expression of inducible NO synthase (iNOS), ATⅡ receptor type 1 (ATR1) and ATR2; Western blotting as employed to examine the iNOS protein expression. Results: (1) LArg increased the content of NO in animals of the operation group, decreased the content of ATⅡ, total protein synthesis, ratio of left ventricle mass/body mass, and expression of ACE mRNA; and LNAME could block the above effect of LArg. (2) Compared with ATⅡ group, ATⅡ+LArg higher content of NO, higher expression of iNOS mRNA and protein, and lower ATR1 mRNA level; the above indices were similar between ATⅡ+LArg+LNAME group and ATⅡ group. The expression of ATR2 mRNA was not significantly different between all the groups. (3) Multiple stepwise regression analysis revealed no relationship of regression between total protein level with blood pressure level or the heart rate. Cardiac NO and ATⅡ contents could serve as predictors for total protein level in the heart. (4) Cardiac NO content was negatively correlated with the cardiac ATⅡ content and ACE and ATR1 expression level.Conclusion: (1) The development of cardiac hypertrophy is closely related to cardiac NO and ATⅡ levels. (2) LArg can increase cardiac NO content through enhancing myocardial iNOS expression; NO can reduce ATⅡ production in myocardiocytes and can inhibit the formation of cardiac hypertrophy by reducing the expression of ACE and ATR1. (3) ATR2 does no participate in the above process.

Key words: L-arginine nitric oxide inducible nitric oxide synthase angiotensinⅡ cardiac hypertrophy