Role of the integrin-linked kinase/PINCH1/alpha-parvin complex in cardiac myocyte hypertrophy
Role of the integrin-linked kinase/PINCH1/alpha-parvin complex in cardiac myocyte hypertrophy
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DOI：
10.1038/labinvest.3700345
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发表时间：
2005-11-01
影响因子：
5
通讯作者：
Sepulveda, JL
中科院分区：
文献类型：
--
作者：
Chen, H;Huang, XYN;Sepulveda, JL
纤维连接蛋白（FN）通过整合素受体发出的外-内信号已被证明在促进心肌细胞肥大中发挥重要作用，并与其他肥厚刺激（如α -肾上腺素能激动剂苯肾上腺素（PE）和机械应变）协同作用。在非肌细胞如成纤维细胞和上皮细胞中，整合素连接激酶（ILK）是参与细胞粘附、运动和存活的关键分子。它在心肌细胞中的作用尚不清楚。在这项研究中，我们证明(1)ILK在新生大鼠心室肌细胞中与PINCH1和α -parvin蛋白形成复合物（IPAP1复合物）；(2)心肌细胞中IPAP1复合物蛋白的定位受FN、PE的刺激，并以整合素β 1依赖的方式通过FN和PE的组合协同作用；(3)缺乏ILK的pinch结合n端（ILK- c）的显性阴性突变体可阻止ILK与α -parvin的共聚体结合，但不能阻止PINCH1；(4)通过增加蛋白/DNA比值、心跳频率和心房利钠肽表达来测量FN-和pe诱导的肥厚，低水平ILK-C刺激了肥厚，高水平ILK-C抑制了肥厚；(5)小鼠新生心室肌细胞中ILK- c的过表达以及ILK基因的缺失可诱导心肌细胞显著凋亡。这些结果表明IPAP1复合物在调节心肌细胞肥大和细胞凋亡抵抗的整合素信号通路中起重要作用。
Outside- in signaling from fibronectin (FN) through integrin receptors has been shown to play an important role in promoting cardiac myocyte hypertrophy and synergizes with other hypertrophic stimuli such as the alpha-adrenergic agonist phenylephrine ( PE) and mechanical strain. The integrin-linked kinase ( ILK) is a critical molecule involved in cell adhesion, motility and survival in nonmyocytes such as fibroblasts and epithelial cells. Its role in cardiac myocytes is unclear. In this study, we demonstrate that ( 1) ILK forms a complex with PINCH1 and alpha-parvin proteins (IPAP1 complex) in neonatal rat ventricular myocytes; ( 2) localization of IPAP1 complex proteins to costameres in cardiac myocytes is stimulated by FN, PE and synergistically by the combination of FN and PE in an integrin beta 1-dependent manner; ( 3) a dominant-negative mutant lacking the PINCH-binding N-terminus of ILK (ILK-C) prevents costamere association of ILK and alpha-parvin, but not PINCH1; ( 4) FN- and PE-induced hypertrophy, measured by increased protein/DNA ratio, beating frequency and atrial natriuretic peptide expression, is stimulated by low levels of ILK-C but repressed by high ILK-C expression; and ( 5) overexpression of ILK-C, as well as deletion of the ILK gene in mouse neonatal ventricular myocytes, induces marked apoptosis of cardiac myocytes. These results suggest that the IPAP1 complex plays an important role in mediating integrin-signaling pathways that regulate cardiac myocyte hypertrophy and resistance to apoptosis.