The Role of the Rho/ROCK Pathway in Ang II and TGF-β1-Induced Atrial Remodeling

• Published in: PloS one Vol. 11; no. 9; p. e0161625
• Main Authors: Liu, Li-Juan, Yao, Feng-Juan, Lu, Gui-Hua, Xu, Cheng-Gui, Xu, Zhe, Tang, Kai, Cheng, Yun-Jiu, Gao, Xiu-Ren, Wu, Su-Hua
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2016; Public Library of Science (PLoS)
• Subjects: Angiotensin; Angiotensin II; Angiotensin II - pharmacology; Animals; Atrial Fibrillation - metabolism; Atrial Remodeling - drug effects; Atrium; Biology and life sciences; Cardiac arrhythmia; Cardiology; Collagen; Connective tissue growth factor; Connective Tissue Growth Factor - genetics; Connective Tissue Growth Factor - metabolism; Connective tissues; Disease Models, Animal; Dogs; Female; Fibrillation; Fibroblasts; Gene expression; Growth factors; Kinases; Male; Medicine and Health Sciences; Research and Analysis Methods; rho GTP-Binding Proteins - genetics; rho GTP-Binding Proteins - metabolism; Rho-associated kinase; rho-Associated Kinases - genetics; rho-Associated Kinases - metabolism; RhoA protein; Rocks; Science; Signal transduction; Signal Transduction - drug effects; Signaling; Simvastatin; Smad2 protein; Transforming Growth Factor beta1 - pharmacology; Transforming growth factor-b1; Ultrasonic imaging; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0161625

To study the role of the Rho/ROCK pathway in Ang II and TGF-β1-induced atrial remodeling. A canine atrial fibrillation (AF) model was established by rapid atrial pacing (RAP) of the left atrium. The roles of TGF-β1, the RhoA/ROCK signaling pathway and connective tissue growth factor (CTGF) in atrial remodeling were studied via both in vitro and in vivo experiments. Each of the dogs that received RAP developed persistent AF within 4 weeks. The mRNA expression levels of TGF-β1 (1.32±0.38), Collagen-I(1.33±0.91), CTGF(5.83±3.71), RhoA(1.23±0.57) and ROCK-1 (1.02±0.27) in the left atrium were significantly increased following 4 weeks of RAP. Angiotensin II (Ang II) induced the proliferation of atrial fibroblasts and up-regulated the expression of both CTGF and ROCK-1 in a dose-dependent manner. Simvastatin and Y27632 reversed Ang II-induced CFs proliferation, as well as ROCK-1(0.89±0.05 and 1.27±0.03, respectively) and CTGF (0.87±0.04 and 0.91±0.02, respectively) expression. The expression mRNA of ROCK-1(1.74±0.13) and CTGF (2.28±0.11) can upregulated by TGF-β1, and down-regulated by Simvastatin (1.22±0.03 vs 2.27±0.11), Y27632 (1.01±0.04 vs 1.64±0.03), Los (1.04±0.11 vs 1.26±0.05), respectively. Losartan and Simvastatin attenuated the effects of TGF-β1, inhibited RhoA activity as opposed to RhoA protein expression. Y27632 had no effect on either the expression or the activity of RhoA. The increased expression of profibrotic factors (CTGF, ROCK1 and Smad2/3) played an important role in our RAP-induced AF model. Increased atrial profibrotic factors involve the activation of either the TGF-β1/RhoA/ROCK-1 or the TGF-β1/Smad2/3 signaling pathway.