Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling
Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling
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DOI：
10.1161/circresaha.107.149047
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发表时间：
2007-08-03
影响因子：
20.1
通讯作者：
Molkentin, Jeffery D.
中科院分区：
文献类型：
--
作者：
Oka, Toru;Xu, Jian;Molkentin, Jeffery D.
心脏细胞外基质是一个动态的结构支撑网络，它既受病理性重塑和肥大性生长的影响，也是其调节因素。在应对病理性损伤时，成年心脏会重新表达分泌型细胞外基质蛋白 periostin（Pn）。在此我们表明，Pn在长期压力过载刺激和心肌梗死之后，对调节心脏肥大反应、间质纤维化以及心室重塑起着关键作用。缺乏编码Pn（Postn）基因的小鼠在心肌梗死后的前10天更容易发生心室破裂，但存活的小鼠显示出较少的纤维化和更好的心室功能。Pn（-/-）小鼠在长期压力过载后也显示出较少的纤维化和肥大，这表明Pn与心脏重塑的调节之间存在密切关系。相反，心脏中Pn的诱导性过表达可保护小鼠在心肌梗死后免于破裂，并随着年龄增长诱导自发性肥大。关于这些变化背后的机制，Pn（-/-）心脏在成纤维细胞功能方面显示出分子程序的改变。实际上，从Pn（-/-）心脏分离出的成纤维细胞在与心肌细胞的黏附方面效果较差，并且其整体基因表达（所有基因的7%）发生了显著变化。这些是首次详细阐述Pn在成年心脏中作为心脏重塑和肥大调节因子功能的遗传学数据。
The cardiac extracellular matrix is a dynamic structural support network that is both influenced by, and a regulator of, pathological remodeling and hypertrophic growth. In response to pathologic insults, the adult heart reexpresses the secreted extracellular matrix protein periostin ( Pn). Here we show that Pn is critically involved in regulating the cardiac hypertrophic response, interstitial fibrosis, and ventricular remodeling following long-term pressure overload stimulation and myocardial infarction. Mice lacking the gene encoding Pn (Postn) were more prone to ventricular rupture in the first 10 days after a myocardial infarction, but surviving mice showed less fibrosis and better ventricular performance. Pn(-/-) mice also showed less fibrosis and hypertrophy following long-term pressure overload, suggesting an intimate relationship between Pn and the regulation of cardiac remodeling. In contrast, inducible overexpression of Pn in the heart protected mice from rupture following myocardial infarction and induced spontaneous hypertrophy with aging. With respect to a mechanism underlying these alterations, Pn(-/-) hearts showed an altered molecular program in fibroblast function. Indeed, fibroblasts isolated from Pn(-/-) hearts were less effective in adherence to cardiac myocytes and were characterized by a dramatic alteration in global gene expression (7% of all genes). These are the first genetic data detailing the function of Pn in the adult heart as a regulator of cardiac remodeling and hypertrophy.