Inhibition of matrix metalloproteinase activity by ACE inhibitors prevents left ventricular remodeling in a rat model of heart failure
Inhibition of matrix metalloproteinase activity by ACE inhibitors prevents left ventricular remodeling in a rat model of heart failure
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DOI：
10.1152/ajpheart.00447.2006
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发表时间：
2007-06-01
影响因子：
4.8
通讯作者：
Janicki, Joseph S.
中科院分区：
文献类型：
--
作者：
Brower, Gregory L.;Levick, Scott P.;Janicki, Joseph S.
血管紧张素转换酶（ACE）抑制剂代表了以左心室（LV）扩张和不适当肥大为特征的心力衰竭的一线药物治疗。ACE抑制剂的作用机制尚不清楚，但有证据表明它们可能通过影响基质金属蛋白酶（MMP）活性而起作用。本研究旨在确定ACE抑制剂是否可以直接调节MMP活性，以及这是否会导致心脏的积极结构和功能适应。为此，MMP-2活性在左心室组织中提取的大鼠下腔静脉（AV）瘘进行了评估，在体外孵育，以及在体内治疗与卡托普利，赖诺普利，或喹那普利。此外，LV大小和功能测定在未经处理的AV瘘大鼠，AV瘘大鼠与赖诺普利治疗（3，5，8周），和年龄匹配的假手术对照。在体外孵育与卡托普利，赖诺普利，喹那普利显着降低NUMP-2的活性。体内处理也是如此。这在MMP-2蛋白的可用池没有减少的情况下发生。长期在体内施用赖诺芬尼也防止LV扩张，减弱心肌肥大，并防止心肌顺应性和收缩性的变化。本文的结果表明，ACE抑制剂阻止MMP-2活性，并且在这样做时，代表了负责防止在心力衰竭的大鼠AV瘘模型中发生的负面结构和功能变化的机制。
Atigiotensin-converting enzyme (ACE) inhibitors represent the front-line pharmacological treatment of heart failure, which is characterized by left ventricular (LV) dilatation and inappropriate hypertrophy. The mechanism of action of ACE inhibitors is still unclear, but evidence Suggests that they may act by influencing matrix metalloproteinase (MMP) activity. This study sought to determine whether ACE inhibitors can directly regulate MMP activity and whether this results in positive structural and functional adaptations to the heart. To this end, MMP-2 activity in LV tissue extracted from rats with an aortocaval (AV) fistula was assessed by in vitro incubation as well as in vivo treatment with captopril, lisinopril, or quinapril. Furthermore, LV size and function were determined in untreated AV fistula rats, AV fistula rats treated with lisinopril (3, 5, and 8 wk), and age-matched sham-operated controls. In vitro incubation with captopril, lisinopril, or quinapril significantly reduced NUMP-2 activity. as did in vivo treatment. This occurred without a reduction in the available pool of MMP-2 protein. Longterm in vivo administration of lisinopnil also prevented LV dilatation, attenuated myocardial hypertrophy, and prevented changes in myocardial compliance and contractility. The results herein demonstrate that ACE inhibitors prevent MMP-2 activity and, in so doing, represent a mechanism responsible for preventing the negative structural and functional changes that occur in the rat AV fistula model of heart failure.