Shimazaki Masashi, Nakamura Kazuto, Kii Isao, Kashima Takeshi, Amizuka Norio, Li Minqi, Saito Mitsuru, Fukuda Keiichi, Nishiyama Takashi, Kitajima Satoshi, Saga Yumiko, Fukayama Masashi, Sata Masataka, Kudo Akira
Department of Biological Information, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
J Exp Med. 2008 Feb 18;205(2):295-303. doi: 10.1084/jem.20071297. Epub 2008 Jan 21.
Acute myocardial infarction (AMI) is a common and lethal heart disease, and the recruitment of fibroblastic cells to the infarct region is essential for the cardiac healing process. Although stiffness of the extracellular matrix in the infarct myocardium is associated with cardiac healing, the molecular mechanism of cardiac healing is not fully understood. We show that periostin, which is a matricellular protein, is important for the cardiac healing process after AMI. The expression of periostin protein was abundant in the infarct border of human and mouse hearts with AMI. We generated periostin(-/-) mice and found no morphologically abnormal cardiomyocyte phenotypes; however, after AMI, cardiac healing was impaired in these mice, resulting in cardiac rupture as a consequence of reduced myocardial stiffness caused by a reduced number of alpha smooth muscle actin-positive cells, impaired collagen fibril formation, and decreased phosphorylation of FAK. These phenotypes were rescued by gene transfer of a spliced form of periostin. Moreover, the inhibition of FAK or alphav-integrin, which blocked the periostin-promoted cell migration, revealed that alphav-integrin, FAK, and Akt are involved in periostin signaling. Our novel findings show the effects of periostin on recruitment of activated fibroblasts through FAK-integrin signaling and on their collagen fibril formation specific to healing after AMI.
急性心肌梗死（AMI）是一种常见的致命性心脏病，成纤维细胞募集至梗死区域对心脏愈合过程至关重要。尽管梗死心肌细胞外基质的硬度与心脏愈合有关，但心脏愈合的分子机制尚未完全明确。我们发现，骨膜蛋白作为一种基质细胞蛋白，对AMI后的心脏愈合过程具有重要作用。在患有AMI的人和小鼠心脏的梗死边界处，骨膜蛋白的表达丰富。我们培育出骨膜蛋白基因敲除（periostin(-/-)）小鼠，未发现心肌细胞表型存在形态学异常；然而，AMI后，这些小鼠的心脏愈合受损，因α平滑肌肌动蛋白阳性细胞数量减少、胶原纤维形成受损及黏着斑激酶（FAK）磷酸化水平降低导致心肌硬度下降，进而引发心脏破裂。通过转导剪接形式的骨膜蛋白基因可挽救这些表型。此外，抑制FAK或αv整合素可阻断骨膜蛋白促进的细胞迁移，这表明αv整合素、FAK和Akt参与了骨膜蛋白信号传导。我们的新发现揭示了骨膜蛋白通过FAK - 整合素信号传导对激活的成纤维细胞募集的影响，以及对AMI后心脏愈合过程中特异性胶原纤维形成的影响。
