Ang II调控心脏成纤维细胞CX43并影响其致心律失常性的关键机制研究

Cardiac fibrobalst (CF) make great contribution to cardiac electrical remodeling through its gap junction mediated electrical coupling with cardiomyocyte. Little is known about the regulation of gap junction in CF. Angiotensin II (Ang II)'s effect on gap junction regulation in cardiomyocyte or myocardium remains controversial. c-Src may participate in this regulation by phosphorylating CX43. However, there is no report yet concerning Ang II's effect on gap junction regulation in CF. Our preliminary study suggested that Ang II could attenuate the pathologically up-regulated CX43 in CF. Taken together, we hypothesize that Ang II could, through AT1R, activate c-Src, which phosphorylate CX43, then down-regulate gap junction in CF and influence its electrical coupling and arrhythmogenecity. We will take advantage of techniques such as RNAi, recommbinant DNA and electrophysiology at the molecular, cell, organ and intact levels to uncover Ang II's effect on CX43 expression, assemly, internalization and function in CF and its effect on CF's arrhythmogenecity, and to explore c-Src’s role in the process and its mechanism of action. With a new point of view, this project will pave the way to further understanding the molecular mechanism of CF's role in cardiac electrical remodeling, and provide a new potential therapeutic target, with a more specific effect, for the prevention of cardiac remodeling and arrhythmia.

心脏成纤维细胞（CF）缝隙连接介导的电学耦联能力上调，参与心脏重构。目前CF缝隙连接的调节机制不明。血管紧张素II（Ang II）对心肌细胞与心肌组织缝隙连接的调节存在争议，其机制可能涉及c-Src对连接蛋白43（CX43）的磷酸化。但Ang II对CF缝隙连接的调节尚无报道。我们前期发现Ang II抑制CF中CX43的病理性上调。综上我们提出假说：Ang II经AT1激活CF中的c-Src，进而磷酸化CX43，下调缝隙连接，影响其电学耦联及致心律失常性。我们将从分子、细胞、组织和动物水平，结合RNAi、重组DNA、电生理等技术，挖掘Ang II对CF中CX43表达、组装、内化与功能的调控作用，及其对CF致心律失常性的影响，并评价c-Src在其中的作用与机制。本项目将从Ang II调控CF缝隙连接这个新视角，阐释CF参与心脏电重构的机制，为心脏重构及心律失常的防治探寻更具针对性的治疗靶点。

心脏成纤维细胞（CF）缝隙连接介导的电学耦联能力上调，参与心脏重构。目前CF缝隙连接的调节机制不明。血管紧张素II（Ang II）对心肌细胞与心肌组织缝隙连接的调节存在争议，其机制可能涉及c-Src对连接蛋白43（CX43）的磷酸化。但Ang II对CF缝隙连接的调节尚无报道。我们前期发现Ang II抑制CF中CX43的病理性上调。本项目我们从分子、细胞、组织和动物水平，结合RNAi、重组DNA、电生理等技术，发现Ang II通过AT1R下调CF中CX43的表达、并通过增加其磷酸化水平，促进其内化，从而下调其电学偶联能力，维持与CF偶联的心肌细胞的静息膜电位。c-Src在其中起重要作用，直接参与CF中CX43的磷酸化与内化。Ang II由于下游效应众多，对心脏的整体作用可增加大鼠的心律失常易感性，特异性抑制c-Src将加强这种作用；特异性激活c-Src，在细胞水平可通过促进CF CX43的内化，下调其电学偶联能力，减少致心律失常基质。CF细胞中Ang II—AT1R—c-Src—CX43通路的发现，有望成为心脏重构及心律失常的防治更针对性的治疗靶点。

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