Rac1-Induced Connective Tissue Growth Factor Regulates Connexin 43 and N-Cadherin Expression in Atrial Fibrillation
Rac1-Induced Connective Tissue Growth Factor Regulates Connexin 43 and N-Cadherin Expression in Atrial Fibrillation
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DOI：
10.1016/j.jacc.2009.08.064
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发表时间：
2010-02-02
影响因子：
24
通讯作者：
Laufs, Ulrich
中科院分区：
文献类型：
--
作者：
Adam, Oliver;Lavall, Daniel;Laufs, Ulrich
目的探讨心房颤动（atrial fibrillation，AF）发生过程中心房结构重构的信号转导机制。方法我们对房颤和窦性心律患者的左心房心肌进行了转录谱分析，并应用培养的原代心脏细胞和过表达结果房颤患者左心房肌结缔组织生长因子（CTGF）的表达较窦性心律患者显著上调。这与纤维化、烟酰胺腺嘌呤二核苷酸磷酸氧化酶、Rac 1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，Rac 1或辛伐他汀的特异性小分子抑制剂完全阻止了血管紧张素II诱导的CTGF、Cx43和N-cadherin表达上调。转染小抑制CTGF核糖核酸阻断Cx43和N-钙粘蛋白的表达。RacET小鼠CTGF、Cx43和N-cadherin蛋白表达上调。口服他汀类药物治疗抑制Rac 1可以预防这些作用，从而确定Rac 1是体内CTGF的关键调节因子。结论数据表明CTGF是AF期间心房结构重塑的重要介质。血管紧张素II通过激活Rac 1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、钙粘蛋白和钙粘蛋白的上调。和间质纤维化，并因此有助于心房结构重构的信号转导。（J Am科尔心脏病学杂志2010; 55：469-80）（C）美国心脏病学会基金会2010年
Objectives We studied the signal transduction of atrial structural remodeling that contributes to the pathogenesis of atrial fibrillation (AF).Background Fibrosis is a hallmark of arrhythmogenic structural remodeling, but the underlying molecular mechanisms are incompletely understood.Methods 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.Results 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.Conclusions 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. (J Am Coll Cardiol 2010; 55: 469-80) (C) 2010 by the American College of Cardiology Foundation