Atorvastatin reduces myocardial fibrosis in a rat model with post-myocardial infarction heart failure by increasing the matrix metalloproteinase-2/tissue matrix metalloproteinase inhibitor-2 ratio
Atorvastatin reduces myocardial fibrosis in a rat model with post-myocardial infarction heart failure by increasing the matrix metalloproteinase-2/tissue matrix metalloproteinase inhibitor-2 ratio
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DOI：
10.3760/cma.j.issn.0366-6999.20123223
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发表时间：
2013-06-05
影响因子：
6.1
通讯作者：
Zhang Wen-qi
中科院分区：
文献类型：
--
作者：
An Zhe;Yang Guang;Zhang Wen-qi
背景 他汀类降胆固醇药物具有一定的非降脂作用，如抑制心肌重构等。但其具体机制尚不清楚。方法结扎冠状动脉左前降支建立大鼠心力衰竭模型,将大鼠分为假手术(SO)组、心肌梗死模型(MI)组和MI-阿托伐他汀组。最后一次给药后记录血流动力学参数的变化。通过检查苏木精和伊红（HE）染色的组织进行组织学诊断。实时定量聚合酶链反应（PCR）测定I型和III型胶原、基质金属蛋白酶2（MMP-2）和组织基质金属蛋白酶抑制剂2（TIMP-2）的表达。进一步培养原代大鼠心脏成纤维细胞，并进行MTT法测定阿托伐他汀对心脏成纤维细胞增殖的影响。结果建立心力衰竭模型，HE染色和Masson三色染色结果显示，心力衰竭组大鼠纤维化组织增生明显，阿托伐他汀组明显减少。实时定量PCR显示，MI组I型、III型胶原、MMP-2、TIMP-2表达显着升高，但MMP-2/TIMP-2比值显着降低。与MI组相比,阿托伐他汀组I、III型胶原表达显着降低,MMP-2表达无变化,TIMP-2表达显着降低,MMP-2/TIMP-2比值升高。我们进一步发现阿托伐他汀显着抑制Ang II诱导的成纤维细胞增殖以及心脏成纤维细胞中I型和III型胶原的表达，同时增加MMP-2/TIMP-2比值。结论这些数据提示阿托伐他汀可以通过增加MMP-2/TIMP-2比值来抑制心脏成纤维细胞增殖并增强胶原降解，从而抑制心肌梗死后心力衰竭大鼠心肌纤维化的形成。
Background The cholesterol-lowering statin drugs have some non-lipid-lowering effects, such as inhibiting myocardial remodeling. However, the underlying mechanism is still unclear.Methods The left anterior descending coronary artery was ligated to establish a rat model of heart failure, and the rats were divided into a sham operation (SO) group, myocardial infarction model (MI) group, and MI-atorvastatin group. Changes in hemodynamic parameters were recorded after the final drug administration. Histological diagnosis was made by reviewing hematoxylin and eosin (HE) stained tissue. Real-time quantitative polymerase chain reaction (PCR) was performed to determine the expressions of type I and type III collagen, matrix metalloproteinase-2 (MMP-2), and tissue matrix metalloproteinase inhibitor-2 (TIMP-2). Further, primary rat cardiac fibroblasts were cultured and the MTT assay was performed to determine the effect of atorvastatin on cardiac fibroblast proliferation.Results The model of heart failure was established and the results of HE staining and Masson's trichrome staining revealed that the rats in the heart failure group showed obvious hyperplasia of fibrotic tissue, which was significantly reduced in the atorvastatin group. Real-time quantitative PCR showed that the MI group showed a significantly increased expression of type I and type III collagen, MMP-2, and TIMP-2, but a significantly reduced MMP-2/TIMP-2 ratio. Compared with the MI group, the atorvastatin group showed significantly reduced expression of type I and III collagen, unchanged expression of MMP-2, significantly reduced expression of TIMP-2, and an increased MMP-2/TIMP-2 ratio. We further found that atorvastatin significantly inhibited the Ang II-induced fibroblast proliferation and the expression of type I and type III collagen in cardiac fibroblasts while increasing the MMP-2/TIMP-2 ratio.Conclusions These data suggest that atorvastatin can inhibit cardiac fibroblast proliferation and enhance collagen degradation by increasing the MMP-2/TIMP-2 ratio, thereby inhibiting the formation of myocardial fibrosis in rats with heart failure after myocardial infarction.