Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum 695011, India.
Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, La Jolla, California 92093.
J Biol Chem. 2019 Dec 20;294(51):19723-19739. doi: 10.1074/jbc.RA119.009744. Epub 2019 Nov 7.
Excessive collagen deposition by myofibroblasts during adverse cardiac remodeling leads to myocardial fibrosis that can compromise cardiac function. Unraveling the mechanisms underlying collagen gene expression in cardiac myofibroblasts is therefore an important clinical goal. The collagen receptors, discoidin domain receptor 2 (DDR2), a collagen-specific receptor tyrosine kinase, and integrin-β1, are reported to mediate tissue fibrosis. Here, we probed the role of DDR2-integrin-β1 cross-talk in the regulation of collagen α1(I) gene expression in angiotensin II (Ang II)-stimulated cardiac fibroblasts. Results from gene silencing/overexpression approaches, electrophoretic mobility shift assays, and ChIP revealed that DDR2 acts via extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK1/2 MAPK)-dependent transforming growth factor-β1 (TGF-β1) signaling to activate activator protein-1 (AP-1) that in turn transcriptionally enhances the expression of collagen-binding integrin-β1 in Ang II-stimulated cardiac fibroblasts. The DDR2-integrin-β1 link was also evident in spontaneously hypertensive rats and DDR2-knockout mice. Further, DDR2 acted via integrin-β1 to regulate α-smooth muscle actin (α-SMA) and collagen type I expression in Ang II-exposed cardiac fibroblasts. Downstream of the DDR2-integrin-β1 axis, α-SMA was found to regulate collagen α1(I) gene expression via the Ca channel, transient receptor potential cation channel subfamily C member 6 (TRPC6), and the profibrotic transcription factor, Yes-associated protein (YAP). This finding indicated that fibroblast-to-myofibroblast conversion is mechanistically coupled to collagen expression. The observation that collagen receptor cross-talk underlies α-SMA-dependent collagen type I expression in cardiac fibroblasts expands our understanding of the complex mechanisms involved in collagen gene expression in the heart and may be relevant to cardiac fibrogenesis.
肌成纤维细胞在不利的心脏重构过程中过度沉积胶原会导致心肌纤维化，从而损害心脏功能。因此，揭示心脏成纤维细胞胶原基因表达的机制是一个重要的临床目标。胶原受体，包括 discoidin 结构域受体 2（DDR2），一种胶原特异性受体酪氨酸激酶，以及整合素-β1，据报道介导组织纤维化。在这里，我们探讨了 DDR2-整合素-β1 相互作用在血管紧张素 II（Ang II）刺激的心肌成纤维细胞中调节胶原 α1（I）基因表达中的作用。基因沉默/过表达方法、电泳迁移率变动分析和 ChIP 结果表明，DDR2 通过细胞外信号调节激酶 1/2 丝裂原活化蛋白激酶（ERK1/2 MAPK）依赖性转化生长因子-β1（TGF-β1）信号传导，激活激活蛋白-1（AP-1），进而转录增强 Ang II 刺激的心肌成纤维细胞中胶原结合整合素-β1 的表达。在自发性高血压大鼠和 DDR2 敲除小鼠中也观察到 DDR2-整合素-β1 联系。此外，DDR2 通过整合素-β1 调节 Ang II 暴露的心肌成纤维细胞中α-平滑肌肌动蛋白（α-SMA）和胶原 I 型的表达。在 DDR2-整合素-β1 轴的下游，发现α-SMA 通过钙通道、瞬时受体电位阳离子通道亚家族 C 成员 6（TRPC6）和致纤维化转录因子 Yes 相关蛋白（YAP）调节胶原 α1（I）基因表达。这一发现表明，成纤维细胞向肌成纤维细胞的转化与胶原表达在机制上是耦合的。胶原受体相互作用是心脏成纤维细胞中依赖α-SMA 的胶原 I 型表达的基础，这扩展了我们对心脏中胶原基因表达涉及的复杂机制的理解，可能与心脏纤维化有关。
