生长分化因子 5 调节心肌梗死后的心脏修复。
Growth differentiation factor 5 regulates cardiac repair after myocardial infarction.
机构信息
Division of Cardiology, University Health Network, Toronto, Ontario, Canada.
出版信息
J Am Coll Cardiol. 2010 Jan 12;55(2):135-43. doi: 10.1016/j.jacc.2009.08.041.
OBJECTIVES
The aim of this study was to examine the function of the bone morphogenic protein growth differentiation factor 5 (Gdf5) in a mouse model of myocardial infarction (MI).
BACKGROUND
The Gdf5 has been implicated in skeletal development, but a potential role in the heart had not been studied.
METHODS
The Gdf5-knockout (KO) and wild-type (WT) mice were subjected to permanent left anterior descending coronary artery (LAD) ligation. Cardiac pathology, function, gene expression levels, and signaling pathways downstream of Gdf5 were examined. Effects of recombinant Gdf5 (rGdf5) were tested in primary cardiac cell cultures.
RESULTS
The WT mice showed increased cardiac Gdf5 levels after MI, with increased expression in peri-infarct cardiomyocytes and myofibroblasts. At 1 and 7 days after MI, no differences were observed in ischemic or infarct areas between WT and Gdf5-KO mice. However, by 28 days after MI, Gdf5-KO mice exhibited increased infarct scar expansion and thinning with decreased arteriolar density compared with WT. The Gdf5-KO hearts also displayed increased left ventricular dilation, with decreased contractility after MI. At 4 days after MI, Gdf5-KO mice exhibited increased cardiomyocyte apoptosis and decreased expression of anti-apoptotic genes Bcl2 and Bcl-xL compared with WT. Unexpectedly, Gdf5-KO hearts displayed increased Smad 1/5/8 phosphorylation but decreased p38-mitogen-activated protein kinase (MAPK) phosphorylation versus WT. The latter was associated with increased collagen gene (Col1a1, Col3a1) expression and fibrosis. In cultures, rGdf5 induced p38-MAPK phosphorylation in cardiac fibroblasts and Smad-dependent increases in Bcl2 and Bcl-xL in cardiomyocytes.
CONCLUSIONS
Increased expression of Gdf5 after MI limits infarct scar expansion in vivo. These effects might be mediated by Gdf5-induced p38-MAPK signaling in fibroblasts and Gdf5-driven Smad-dependent pro-survival signaling in cardiomyocytes.
目的
本研究旨在探讨骨形态发生蛋白生长分化因子 5（Gdf5）在心肌梗死（MI）小鼠模型中的作用。
背景
Gdf5 参与骨骼发育，但尚未研究其在心脏中的潜在作用。
方法
对 Gdf5 敲除（KO）和野生型（WT）小鼠进行永久性左前降支冠状动脉（LAD）结扎。检测心脏病理、功能、Gdf5 下游基因表达水平和信号通路。测试重组 Gdf5（rGdf5）对原代心肌细胞培养物的影响。
结果
WT 小鼠在 MI 后心脏 Gdf5 水平升高，梗死周边心肌细胞和成纤维细胞表达增加。在 MI 后 1 天和 7 天，WT 和 Gdf5-KO 小鼠的缺血或梗死面积无差异。然而，在 MI 后 28 天，与 WT 相比，Gdf5-KO 小鼠的梗死瘢痕扩张和变薄增加，小动脉密度降低。Gdf5-KO 心脏在 MI 后也表现出左心室扩张增加，收缩功能降低。在 MI 后 4 天，与 WT 相比，Gdf5-KO 小鼠的心肌细胞凋亡增加，抗凋亡基因 Bcl2 和 Bcl-xL 的表达减少。出乎意料的是，与 WT 相比，Gdf5-KO 心脏的 Smad1/5/8 磷酸化增加，p38-丝裂原激活蛋白激酶（MAPK）磷酸化减少。后者与胶原基因（Col1a1、Col3a1）表达增加和纤维化有关。在培养物中，rGdf5 诱导心肌成纤维细胞中 p38-MAPK 磷酸化和 Gdf5 诱导的 Smad 依赖性 Bcl2 和 Bcl-xL 在心肌细胞中的增加。
结论
MI 后 Gdf5 表达增加可限制体内梗死瘢痕扩张。这些作用可能是由 Gdf5 诱导的成纤维细胞中 p38-MAPK 信号传导和 Gdf5 驱动的心肌细胞中 Smad 依赖性存活信号传导介导的。
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