Abstract
ObjectivesTo study the role of the Rho/ROCK pathway in Ang II and TGF-β1-induced atrial remodeling.Methods and ResultsA 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.ConclusionsThe 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.
Highlights
Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice and is common among the elderly, with an annual incidence of approximately 3% among patients 85 years of age and older[1]
The results indicated that TGF-β1 and RhoA/Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK)-1 are both downstream factors of Angiotensin II (Ang II) in atrial CFs (Fig 4H–4J)
We demonstrated that Ang II induced the proliferation of neonatal Sprague Dawley (SD) rat atrial cells and increased the expression of both ROCK-1 and connective tissue growth factor (CTGF) in both a concentration and a time-dependent manner
Summary
Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice and is common among the elderly, with an annual incidence of approximately 3% among patients 85 years of age and older[1]. AF is often triggered by rapid electrical activity originating from small areas that are typically located between the left atrium and the pulmonary veins[3, 4]. New treatment approaches such as catheter ablation have been used to successfully treat AF. Fibrosis initially serves as an important adaptive response; increased atrial fibrosis contributes to the development of conduction abnormalities, resulting in electrical vulnerability. The interrelated pathways apparently include the rennin-angiotensin system, TGF-β1[7], ERK[8] and oxidative stress pathways[9]
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