β3 integrin in cardiac fibroblast is critical for extracellular matrix accumulation during pressure overload hypertrophy in mouse.
β3 integrin in cardiac fibroblast is critical for extracellular matrix accumulation during pressure overload hypertrophy in mouse.
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DOI：
10.1371/journal.pone.0045076
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kuppuswamy D
中科院分区：
文献类型：
--
作者：
Balasubramanian S;Quinones L;Kasiganesan H;Zhang Y;Pleasant DL;Sundararaj KP;Zile MR;Bradshaw AD;Kuppuswamy D
粘附受体β3整联蛋白调节各种组织中的多种细胞功能。由于β3整合素参与细胞外基质（ECM）重塑，我们试图通过使用野生型（WT）和β3整合素缺失（β3−/−）小鼠进行体内压力超负荷（PO）和体外原代心脏成纤维细胞表型研究来探索β3整合素在心脏纤维化中的作用。与WT小鼠相比，β3−/−小鼠在通过横主动脉缩窄（TAC）进行的压力超负荷肥大4周后，显示间质纤维连接蛋白和胶原蛋白的蓄积显著减少。此外，在PO的早期时间点，来自β3−/−小鼠的压力过载LV表现出成纤维细胞增殖和成纤维细胞特异性蛋白-1（FSP 1）表达水平降低。为了测试在β3−/−小鼠中观察到的ECM积累受损是否是由于心脏成纤维细胞功能受损，我们分析了WT和β3−/−小鼠的原代心脏成纤维细胞对ECM蛋白的粘附、细胞扩散、增殖和迁移，以响应血小板衍生生长因子-BB（PDGF，一种已知促进纤维化的生长因子）刺激。我们的结果表明，β3−/−心脏成纤维细胞表现出细胞-基质粘附、细胞铺展、增殖和迁移的显著减少。此外，在β3−/−细胞中，PDGF刺激后，PDGF受体相关酪氨酸激酶和非受体酪氨酸激酶Pyk 2的活化受损。腺病毒表达显性阴性形式的Pyk 2（Y 402 F）导致纤连蛋白的积累减少。这些结果表明，心脏成纤维细胞中β3整合素介导的Pyk 2信号传导在PO诱导的心脏纤维化中起关键作用。
The adhesion receptor β3 integrin regulates diverse cellular functions in various tissues. As β3 integrin has been implicated in extracellular matrix (ECM) remodeling, we sought to explore the role of β3 integrin in cardiac fibrosis by using wild type (WT) and β3 integrin null (β3−/−) mice for in vivo pressure overload (PO) and in vitro primary cardiac fibroblast phenotypic studies. Compared to WT mice, β3−/− mice upon pressure overload hypertrophy for 4 wk by transverse aortic constriction (TAC) showed a substantially reduced accumulation of interstitial fibronectin and collagen. Moreover, pressure overloaded LV from β3−/− mice exhibited reduced levels of both fibroblast proliferation and fibroblast-specific protein-1 (FSP1) expression in early time points of PO. To test if the observed impairment of ECM accumulation in β3−/− mice was due to compromised cardiac fibroblast function, we analyzed primary cardiac fibroblasts from WT and β3−/− mice for adhesion to ECM proteins, cell spreading, proliferation, and migration in response to platelet derived growth factor-BB (PDGF, a growth factor known to promote fibrosis) stimulation. Our results showed that β3−/− cardiac fibroblasts exhibited a significant reduction in cell-matrix adhesion, cell spreading, proliferation and migration. In addition, the activation of PDGF receptor associated tyrosine kinase and non-receptor tyrosine kinase Pyk2, upon PDGF stimulation were impaired in β3−/− cells. Adenoviral expression of a dominant negative form of Pyk2 (Y402F) resulted in reduced accumulation of fibronectin. These results indicate that β3 integrin-mediated Pyk2 signaling in cardiac fibroblasts plays a critical role in PO-induced cardiac fibrosis.
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