Transient Receptor Potential Canonical 3 and Nuclear Factor of Activated T Cells C3 Signaling Pathway Critically Regulates Myocardial Fibrosis
Transient Receptor Potential Canonical 3 and Nuclear Factor of Activated T Cells C3 Signaling Pathway Critically Regulates Myocardial Fibrosis
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DOI：
10.1089/ars.2018.7545
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发表时间：
2018-11-29
影响因子：
6.6
通讯作者：
Fares, Nassim
中科院分区：
文献类型：
--
作者：
Saliba, Youakim;Jebara, Victor;Fares, Nassim
目的：心脏成纤维细胞（CF）正在成为心肌纤维化（MF）的主要贡献者，而心肌纤维化是许多心脏病病因的最终共同途径。在这里，我们研究了啮齿动物和人类心室 CF 中瞬时受体电位规范 3 (TRPC3) 通道和激活 T 细胞核因子 c3 (NFATc3) 信号传导的功能相关性，以及它们的调节是否会限制 MF。结果：TRPC3 和 NFATc3 之间的正反馈环驱动大鼠心室 CF 纤维化表型。在这些细胞中，多酚（葡萄果渣多酚提取物 [P.E.]）通过直接调节 TRPC3 通道和随后的 NFATc3 信号传导，减少基础和血管紧张素 II 介导的 Ca2+ 进入，消除肌成纤维细胞分化、纤维化和炎症，以及氧化应激相关表型。 N(omega)-硝基-l-精氨酸甲酯 (l-NAME) 高血压大鼠通过诱导激活的 CF 中的胚胎心外膜祖转录因子而发生冠状血管周围、心外膜下和间质纤维化。体育运动治疗通过调节 TRPC3-NFATc3 通路减少心室 CF 激活，并改善 l-NAME 高血压大鼠的超声心动图参数、心脏应激标志物和 MF，与血压调节无关。此外，基因缺失（TRPC3（-/-））和用N-[4-[3,5-双（三氟甲基）-1H-吡唑-1-基]苯基]-4-甲基-苯磺酰胺（Pyr10）阻断药理通道可减弱l-NAME高血压小鼠的心室CF激活和MF。最后，TRPC3 存在于人心室 CF 中，并在 MF 中上调，而 TRPC3-NFATc3 的药理学调节可减少增殖和胶原蛋白分泌。创新与结论：我们证明 TRPC3-NFATc3 信号传导受 P.E. 调节。并严格调节心室 CF 表型和 MF。这些发现强烈支持通过 TRPC3 靶向的 P.E 作为 MF 管理的潜在且有趣的疗法。
Aims: Cardiac fibroblasts (CFs) are emerging as major contributors to myocardial fibrosis (MF), a final common pathway of many etiologies of heart disease. Here, we studied the functional relevance of transient receptor potential canonical 3 (TRPC3) channels and nuclear factor of activated T cells c3 (NFATc3) signaling in rodent and human ventricular CFs, and whether their modulation would limit MF. Results: A positive feedback loop between TRPC3 and NFATc3 drove a rat ventricular CF fibrotic phenotype. In these cells, polyphenols (extract of grape pomace polyphenol [P.E.]) decreased basal and angiotensin II-mediated Ca2+ entries through a direct modulation of TRPC3 channels and subsequently NFATc3 signaling, abrogating myofibroblast differentiation, fibrosis and inflammation, as well as an oxidative stress-associated phenotype. N(omega)-nitro-l-arginine methyl ester (l-NAME) hypertensive rats developed coronary perivascular, sub-epicardial, and interstitial fibrosis with induction of embryonic epicardial progenitor transcription factors in activated CFs. P.E. treatment reduced ventricular CF activation by modulating the TRPC3-NFATc3 pathway, and it ameliorated echocardiographic parameters, cardiac stress markers, and MF in l-NAME hypertensive rats independently of blood pressure regulation. Further, genetic deletion (TRPC3(-/-)) and pharmacological channel blockade with N-[4-[3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-4-methyl-benzenesulfonamide (Pyr10) blunted ventricular CF activation and MF in l-NAME hypertensive mice. Finally, TRPC3 was present in human ventricular CFs and upregulated in MF, whereas pharmacological modulation of TRPC3-NFATc3 decreased proliferation and collagen secretion. Innovation and Conclusion: We demonstrate that TRPC3-NFATc3 signaling is modulated by P.E. and critically regulates ventricular CF phenotype and MF. These findings strongly argue for P.E., through TRPC3 targeting, as potential and interesting therapeutics for MF management.