血管紧张素转换酶抑制剂、血管紧张素II 1型受体阻滞剂及其联合应用对大鼠心肌梗死后心室重构的影响。

Effects of angiotensin converting enzyme inhibitor, angiotensin II type I receptor blocker and their combination on postinfarcted ventricular remodeling in rats.

作者信息

Zhang Rui-ying, Wang Lan-feng, Zhang Lei, Meng Xiang-ning, Li Shao-jun, Wang Wu-ru

机构信息

Department of Cardiology First Clinical Hospital, Harbin Medical University, Harbin 150001, China.

出版信息

Chin Med J (Engl). 2006 Apr 20;119(8):649-55.

PMID:16635409

Abstract

BACKGROUND

Transforming growth factor (TGF) beta(1)-Smads signal plays an important role in cardiac remodeling following myocardial infarction (MI). In addition, both angiotensin converting enzyme inhibitor (ACEI) and angiotensin II type I receptor blocker (ARB) can effectively prevent left ventricular remodeling. The current study focused on whether the combination of ACEI and ARB is more beneficial for preventing ventricular remodeling and whether Smad proteins mediate this beneficial effect.

METHODS

MI was induced by ligating the left anterior descending coronary artery in rats. Twenty-four hours after ligation, the survived rats were randomly divided into five groups and treated for 8 weeks: placebo group, ACEI group (benazepril 10 mg.kg(-1).d(-1)), ARB group (irbesartan 50 mg.kg(-1).d(-1)), ACEI + ARB group (benazepril 10 mg.kg(-1).d(-1) + irbesartan 50 mg.kg(-1).d(-1)) and control group (sham-operated rats). After 8 weeks, we examined the following indexes: the ratio of ventricular weight to body weight (VW/BW), left ventricular end diastolic dimension (LVDd), ejection fraction (EF), fractional shortening (FS), ratio of E-wave to A-wave velocity, collagen of noninfarcted zone, the mRNA expression of TGFbeta(1), Smad 2, and Smad 3 by RT-PCR in noninfarcted zone, the protein expression of Smad 2 and Smad 3 in noninfarcted zone by Western blot.

RESULTS

VW/BW significantly increased in the placebo groups compared with that in the control group (P < 0.01). This increase was limited in ACEI, ARB, and combined groups (P < 0.01 compared with placebo group). There was no significant difference among the three actively treated groups. Collagen was increased in placebo group (5.68 +/- 0.5)% compared with that in control group (P < 0.01). ACEI, ARB and combined treatment attenuated this increase of collagen [(4.3 +/- 0.5)%, (3.5 +/- 0.5)%, (3.2 +/- 0.4)%] in comparison with that in placebo group (P < 0.01 respectively). Combined treatment showed more significant effect on collagen deposition. EF and FS significantly decreased, LVDd and E/A significantly increased in placebo group compared with that in control group (P < 0.01 respectively). ACEI, ARB and combined treatment ameliorated these indexes (P < 0.01 compared with placebo group). The mRNA expression of TGFbeta(1), Smad 2, and Smad 3 (0.700 +/- 0.045, 0.959 +/- 0.037 and 0.850 +/- 0.051) increased in placebo group compared with that in control group (P < 0.01). ACEI, ARB and combined treatment normalized the increase (P < 0.01). Furthermore, ARB and combined treatment proved to be more effective in decreasing TGF beta(1) and Smad mRNA expression than ACEI treatment (P < 0.01). The expression of Smad 2 and Smad 3 protein increased in placebo group compared with that in control group (P < 0.01). ACEI, ARB and combined treatment normalized the increase (P < 0.01). Furthermore, ARB and combined treatment proved to be more effective than ACEI alone (P < 0.01).

CONCLUSIONS

TGFbeta(1)-Smads signal activation is correlated with ventricular remodeling following MI. ACEI and ARB treatment prevents ventricular remodeling by inhibiting expression of Smad 2 and Smad 3. ARB and combined treatment are more effective than ACEI alone.

摘要

背景

转化生长因子（TGF）β1 - Smads信号在心肌梗死（MI）后的心脏重塑中起重要作用。此外，血管紧张素转换酶抑制剂（ACEI）和血管紧张素II 1型受体阻滞剂（ARB）均可有效预防左心室重塑。本研究聚焦于ACEI与ARB联合使用是否更有利于预防心室重塑，以及Smad蛋白是否介导这种有益作用。

方法

通过结扎大鼠左冠状动脉前降支诱导MI。结扎后24小时，将存活的大鼠随机分为五组并治疗8周：安慰剂组、ACEI组（苯那普利10 mg·kg-1·d-1）、ARB组（厄贝沙坦50 mg·kg-1·d-1）、ACEI + ARB组（苯那普利10 mg·kg-1·d-1 + 厄贝沙坦50 mg·kg-1·d-1）和对照组（假手术大鼠）。8周后，检测以下指标：心室重量与体重之比（VW/BW）、左心室舒张末期内径（LVDd）、射血分数（EF）、缩短分数（FS）、E波与A波速度之比、非梗死区胶原蛋白、通过逆转录聚合酶链反应（RT-PCR）检测非梗死区TGFβ1、Smad 2和Smad 3的mRNA表达、通过蛋白质免疫印迹法检测非梗死区Smad 2和Smad 3的蛋白表达。

结果

与对照组相比，安慰剂组的VW/BW显著增加（P < 0.01）。ACEI组、ARB组和联合治疗组的这种增加受到限制（与安慰剂组相比P < 0.01）。三个积极治疗组之间无显著差异。与对照组相比，安慰剂组的胶原蛋白增加（5.68 ± 0.5）%（P < 0.01）。与安慰剂组相比，ACEI组、ARB组和联合治疗组减轻了胶原蛋白的这种增加[（4.3 ± 0.5）%、（3.5 ± 0.5）%、（3.2 ± 0.4）%]（分别为P < 0.01）。联合治疗对胶原蛋白沉积的作用更显著。与对照组相比，安慰剂组的EF和FS显著降低，LVDd和E/A显著增加（分别为P < 0.01）。ACEI组、ARB组和联合治疗改善了这些指标（与安慰剂组相比P < 0.01）。与对照组相比，安慰剂组TGFβ1、Smad 2和Smad 3的mRNA表达增加（0.700 ± 0.045、0.959 ± 0.037和0.850 ± 0.051）（P < 0.01）。ACEI组、ARB组和联合治疗使这种增加恢复正常（P < 0.01）。此外，ARB组和联合治疗在降低TGFβ1和Smad mRNA表达方面比ACEI治疗更有效（P < 0.01）。与对照组相比，安慰剂组Smad 2和Smad 3蛋白表达增加（P < 0.01）。ACEI组、ARB组和联合治疗使这种增加恢复正常（P < 0.01）。此外，ARB组和联合治疗比单独使用ACEI更有效（P < 0.01）。