Lung remodeling and pulmonary hypertension after myocardial infarction: pathogenic role of reduced caveolin expression
Lung remodeling and pulmonary hypertension after myocardial infarction: pathogenic role of reduced caveolin expression
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DOI：
10.1016/j.cardiores.2004.05.018
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发表时间：
2004-09-01
影响因子：
10.8
通讯作者：
Lisanti, MP
中科院分区：
文献类型：
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作者：
Jasmin, JF;Mercier, I;Lisanti, MP
目的：肺动脉高压和肺结构重塑是充血性心力衰竭(CHF)常见的并发症。然而，CHF诱导的肺高压和肺重塑的分子机制仍不清楚。Caveolins(Cav-1、-2和-3)是质膜囊泡内陷的主要结构蛋白，称为小窝。小窝蛋白-1基因纯合子缺失(Cav-1(-/-))的小鼠已被证明发生扩张型心肌病、肺高压和肺结构重塑，其特征是肺泡间隔增厚和细胞肥大。然而，这些观察结果与肺高压和肺重塑发病机制的生理学相关性仍有待确定。方法和结果：在这里，我们利用大鼠心肌梗死(MI)模型，研究了内源性小窝蛋白在肺高压和肺结构重塑发展过程中的自然行为。雄性Wistar大鼠结扎左冠状动脉前支诱导心肌梗死。心肌梗死后2周，麻醉大鼠，测量血流动力学和形态计量学指标。心肌梗死大鼠出现明显的肺高压、肺结构重构和右室肥厚(RVH)。免疫印迹分析和免疫组织化学均显示心肌梗死后大鼠肺组织中Cav-1和Cav-2的表达下调至几乎检测不到的水平。从机制上讲，小窝蛋白表达的减少与信号转导和转录激活因子-3(STAT3)酪氨酸磷酸化增加以及细胞周期蛋白D1和D3表达上调有关。我们还发现，在Cav-1(-/-)和Cav-2(-/-)缺陷小鼠的肺组织样本中，STAT3过度磷酸化，细胞周期蛋白D1和D3水平显著上调。结论：心肌梗死大鼠肺组织Cav-1和Cav-2表达下调可能是导致STAT3/Cyclins通路激活的启动机制，最终导致肺高压的发生和肺结构重塑。(C)2004年欧洲心脏病学会。爱思唯尔出版公司版权所有。
Objectives: Pulmonary hypertension (PH) and lung structural remodeling are frequent complications of congestive heart failure (CHF). Yet, the molecular mechanisms involved in CHF-induced PH and lung remodeling remain unknown. Caveolins (Cav-1, -2 and -3) are the principal structural proteins of the vesicular invaginations of the plasma membrane, termed caveolae. Mice with homozygous deletion of the caveolin-1 gene (Cav-1(-/-)) have been shown to develop dilated cardiomyopathy, PH and lung structural remodeling, characterized by hypercellularity and thickening of the alveolar septa. However, the physiological relevance of these observations for the pathogenesis of PH and lung remodeling remains to be determined. Methods and results: Here, we investigate the natural behavior of the endogenous caveolin proteins during the development of PH and lung structural remodeling, using a rat model of myocardial infarction (MI). MI was induced in male Wistar rats by ligating the left anterior coronary artery. Two weeks post-MI, rats were anesthetized and hemodynamic and morphometric measurements were obtained. Rats subjected to MI developed marked PH, lung structural remodeling and right ventricular hypertrophy (RVH). Both immunoblot analysis and immunohistochemistry dramatically show that Cav-1 and Cav-2 expression is downregulated to almost undetectable levels in the lungs of post-MI rats. Mechanistically, the reduced expression of caveolins was associated with the increased tyrosine-phosphorylation of the signal transducer and activator of transcription-3 (STAT3) and the upregulation of cyclin D1 and D3 expression. We also show that STAT3 is hyperphosphorylated, and cyclin D1 and D3 levels are dramatically upregulated, in lung tissue samples derived from Cav-1 (-/-)- and Cav-2 (-/-)-deficient mice. Conclusions: Thus, down-modulation of pulmonary Cav-1 and Cav-2 expression in rats subjected to MI may represent an initiating mechanism leading to the activation of the STAT3/Cyclins pathway and, ultimately, to the development of PH and lung structural remodeling. (C) 2004 European Society of Cardiology. Published by Elsevier B.V All rights reserved.