Pravastatin increases survival and suppresses an increase in myocardial matrix metalloproteinase activity in a rat model of heart failure
Pravastatin increases survival and suppresses an increase in myocardial matrix metalloproteinase activity in a rat model of heart failure
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DOI：
10.1016/j.cardiores.2005.08.001
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发表时间：
2006-02-15
影响因子：
10.8
通讯作者：
Yokota, M
中科院分区：
文献类型：
--
作者：
Ichihara, S;Noda, A;Yokota, M
目的：氧化应激与心力衰竭的发病机制有关，并影响基质金属蛋白酶（MMPs）的活性。我们现在在大鼠模型中研究了MMPs及其组织抑制剂（TIMPs）在代偿性左心室肥厚向心力衰竭转变中的作用，以及普伐他汀对这一转变的影响。方法：从7周龄开始，采用高盐（8% NaCl）饲料喂养达尔盐敏感大鼠，同时给予普伐他汀（50或100 mg/kg / d）或载药。结果：普伐他汀对12或18周龄时明显的左室肥厚没有减轻作用。然而，大剂量本品可显著改善18周龄大鼠的舒张功能指标（早期舒张心肌速度）和收缩功能指标（左室分数缩短），提高存活率。它还能防止高盐饮食引起的左心室还原性谷胱甘肽与氧化性谷胱甘肽比例的下降和NADPH氧化酶活性的增加。18周龄时左室组织中MMP2和MMP9的活性以及TIMP1和TIMP2的丰度升高，普伐他汀也阻止了这些变化。结论：普伐他汀虽不能减轻左室肥厚，但能阻止模型大鼠由代偿性肥厚向心力衰竭的转变。普伐他汀的这种作用可能是由于心脏氧化应激水平和MMP活性的降低。(c) 2005年欧洲心脏病学会。Elsevier B.V.版权所有。
Objectives: Oxidative stress is implicated in the pathogenesis of heart failure and affects the activity of matrix metalloproteinases (MMPs). We have now investigated the role of MMPs and their tissue inhibitors (TIMPs) in the transition from compensated left ventricular (LV) hypertrophy to heart failure as well as the effects of pravastatin on this transition in a rat model.Methods: Dahl salt-sensitive rats were fed a high-salt (8% NaCl) diet and treated with pravastatin (50 or 100 mg/kg per day) or vehicle from 7 weeks of age.Results: Pravastatin did not attenuate LV hypertrophy apparent at 12 or 18 weeks of age. However, the high dose of this drug markedly improved indices of diastolic function (early diastolic myocardial velocity) and systolic function (LV fractional shortening) at 18 weeks of age and increased the survival rate. It also prevented a decrease in the ratio of reduced to oxidized glutathione and an increase in NADPH oxidase activity in the left ventricle induced by the high-salt diet. The activities of MMP2 and MMP9 and the abundance of TIMP1 and TIMP2 in LV tissue were increased at 18 weeks of age, and pravastatin also prevented these changes.Conclusion: Although pravastatin did not attenuate LV hypertrophy, it prevented the transition from compensated hypertrophy to heart failure in this rat model. This effect of pravastatin may result from a reduction both in the level of oxidative stress and in MMP activity in the heart. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.