The Role of the Rho/ROCK Pathway in Ang II and TGF-β1-Induced Atrial Remodeling.
OBJECTIVE
To study the role of the Rho/ROCK pathway in Ang II and TGF-β1-induced atrial remodeling.


RESULTS
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.


CONCLUSIONS
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.
Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Li-Juan
LJ
Liu
Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Feng-Juan
FJ
Yao
Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Gui-Hua
GH
Lu
Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Cheng-Gui
CG
Xu
Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Zhe
Z
Xu
Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Kai
K
Tang
Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Yun-Jiu
YJ
Cheng
Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Xiu-Ren
XR
Gao
Department of Cardiology and Department of Ultrasonography (Feng-Juan Yao), the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Su-Hua
SH
Wu
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism; D064752:Atrial Remodeling / Q000187:drug effects*; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D008297:Male; D015398:Signal Transduction / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins