Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarland, Homburg/Saar, Germany.
J Am Coll Cardiol. 2010 Feb 2;55(5):469-80. doi: 10.1016/j.jacc.2009.08.064.
We studied the signal transduction of atrial structural remodeling that contributes to the pathogenesis of atrial fibrillation (AF).
Fibrosis is a hallmark of arrhythmogenic structural remodeling, but the underlying molecular mechanisms are incompletely understood.
We performed transcriptional profiling of left atrial myocardium from patients with AF and sinus rhythm and applied cultured primary cardiac cells and transgenic mice with overexpression of constitutively active V12Rac1 (RacET) in which AF develops at old age to characterize mediators of the signal transduction of atrial remodeling.
Left atrial myocardium from patients with AF showed a marked up-regulation of connective tissue growth factor (CTGF) expression compared with sinus rhythm patients. This was associated with increased fibrosis, nicotinamide adenine dinucleotide phosphate oxidase, Rac1 and RhoA activity, up-regulation of N-cadherin and connexin 43 (Cx43) expression, and increased angiotensin II tissue concentration. In neonatal rat cardiomyocytes and fibroblasts, a specific small molecule inhibitor of Rac1 or simvastatin completely prevented the angiotensin II-induced up-regulation of CTGF, Cx43, and N-cadherin expression. Transfection with small-inhibiting CTGF ribonucleic acid blocked Cx43 and N-cadherin expression. RacET mice showed up-regulation of CTGF, Cx43, and N-cadherin protein expression. Inhibition of Rac1 by oral statin treatment prevented these effects, identifying Rac1 as a key regulator of CTGF in vivo.
The data identify CTGF as an important mediator of atrial structural remodeling during AF. Angiotensin II activates CTGF via activation of Rac1 and nicotinamide adenine dinucleotide phosphate oxidase, leading to up-regulation of Cx43, N-cadherin, and interstitial fibrosis and therefore contributing to the signal transduction of atrial structural remodeling.
我们研究了导致心房颤动（AF）发病机制的心房结构重构的信号转导。
纤维化是心律失常性结构重构的标志，但潜在的分子机制尚不完全清楚。
我们对来自 AF 患者和窦性心律患者的左心房心肌进行了转录谱分析，并应用原代心脏细胞培养和过表达组成型激活 V12Rac1（RacET）的转基因小鼠，其中老年时会发生 AF，以表征心房重构信号转导的介质。
与窦性心律患者相比，AF 患者的左心房心肌中 CTGF 的表达明显上调。这与纤维化、烟酰胺腺嘌呤二核苷酸磷酸氧化酶、Rac1 和 RhoA 活性增加、N-钙粘蛋白和连接蛋白 43（Cx43）表达上调以及血管紧张素 II 组织浓度增加有关。在新生大鼠心肌细胞和成纤维细胞中，Rac1 的特异性小分子抑制剂或辛伐他汀完全阻止了血管紧张素 II 诱导的 CTGF、Cx43 和 N-钙粘蛋白表达上调。小干扰 CTGF 核糖核酸转染阻断了 Cx43 和 N-钙粘蛋白的表达。RacET 小鼠表现出 CTGF、Cx43 和 N-钙粘蛋白蛋白表达上调。口服他汀类药物抑制 Rac1 可防止这些作用，表明 Rac1 是体内 CTGF 的关键调节剂。
数据表明 CTGF 是 AF 期间心房结构重构的重要介质。血管紧张素 II 通过激活 Rac1 和烟酰胺腺嘌呤二核苷酸磷酸氧化酶激活 CTGF，导致 Cx43、N-钙粘蛋白和间质纤维化上调，从而促进心房结构重构的信号转导。
