TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals.
TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals.
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DOI：
10.1016/j.yjmcc.2012.10.016
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发表时间：
2013-01
影响因子：
5
通讯作者：
Thodeti CK
中科院分区：
文献类型：
--
作者：
Adapala RK;Thoppil RJ;Luther DJ;Paruchuri S;Meszaros JG;Chilian WM;Thodeti CK
心肌成纤维细胞分化为高分泌肌成纤维细胞的表型转换对心肌梗死后的心脏重塑至关重要。在伤口愈合过程中，肌成纤维细胞通过分泌和组织细胞外基质（ECM）促进心肌的伤口修复。然而，肌成纤维细胞分化的分子机制尚不清楚。TGF-β已被证明促进分化，结合心脏中强大的机械环境，我们假设机械转导和TGF-β信号通路在心脏成纤维细胞向肌成纤维细胞的分化中发挥积极作用。在这里，我们发现机械敏感离子通道TRPV4是TGF-β1诱导的心脏成纤维细胞向肌成纤维细胞分化所必需的。通过α-SMA掺入应力纤维，我们发现TRPV4特异性拮抗剂AB159908和TRPV4的siRNA敲低显著抑制tgf - β1诱导的分化。此外，我们发现TGF-β1诱导的肌成纤维细胞分化依赖于ECM僵硬，这一反应被TRPV4阻断后减弱。最后，与未处理的对照组相比，TGF-β1处理的成纤维细胞表现出增强的TRPV4表达和TRPV4介导的钙内流。综上所述，这些结果首次表明，机械敏感离子通道TRPV4通过整合TGF-β1和机械因子的信号来调节心肌成纤维细胞向肌成纤维细胞的分化。
The phenotypic switch underlying the differentiation of cardiac fibroblasts into hypersecretory myofibroblasts is critical for cardiac remodeling following myocardial infarction. Myofibroblasts facilitate wound repair in the myocardium by secreting and organizing extracellular matrix (ECM) during the wound healing process. However, the molecular mechanisms involved in myofibroblast differentiation are not well known. TGF-β has been shown to promote differentiation and this, combined with the robust mechanical environment in the heart, lead us to hypothesize that the mechanotransduction and TGF-β signaling pathways play active roles in the differentiation of cardiac fibroblasts to myofibroblasts. Here, we show that the mechanosensitve ion channel TRPV4 is required for TGF-β1-induced differentiation of cardiac fibroblasts into myofibroblasts. We found that the TRPV4-specific antagonist AB159908 and siRNA knockdown of TRPV4 significantly inhibited TGFβ1-induced differentiation as measured by incorporation of α-SMA into stress fibers. Further, we found that TGF-β1-induced myofibroblast differentiation was dependent on ECM stiffness, a response that was attenuated by TRPV4 blockade. Finally, TGF-β1 treated fibroblasts exhibited enhanced TRPV4 expression and TRPV4-mediated calcium influx compared to untreated controls. Taken together these results suggest for the first time that the mechanosensitive ion channel, TRPV4, regulates cardiac fibroblast differentiation to myofibroblasts by integrating signals from TGF-β1 and mechanical factors.
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影响因子：
5
作者：
Flack, EC;Lindsey, ML;Spinale, FG
通讯作者：
Spinale, FG
影响因子：
4.8
作者：
Carracedo, Sergio;Lu, Ning;Gullberg, Donald
通讯作者：
Gullberg, Donald
DOI：
10.1126/stke.2002.119.pe6
发表时间：
2002-02-12
期刊：
Science's STKE : signal transduction knowledge environment
影响因子：
--
作者：
Alenghat, Francis J;Ingber, Donald E
通讯作者：
Ingber, Donald E
DOI：
10.1073/pnas.0800835105
发表时间：
2008-08-12
影响因子：
11.1
作者：
Ghosh, Kaustabh;Thodeti, Charles K.;Ingber, Donald E.
通讯作者：
Ingber, Donald E.
DOI：
10.1152/ajpheart.00142.2011
发表时间：
2011-09-01
影响因子：
4.8
作者：
Adapala, Ravi K.;Talasila, Phani K.;Thodeti, Charles K.
通讯作者：
Thodeti, Charles K.