Abstract 19515: Tachycardia of Atrial Myocytes Induces Expression of Transforming Growth Factor beta1 and Procollagen in Atrial Fibroblasts Through Paracrine Angiotensin II and Reactive Oxygen Species
Aims: To investigate the molecular mechanism of rapid depolarization-induced atrial fibrosis.
Methods and Results: We used a direct atrial myocye-fibroblast contact coculture and a fibroblast-specific transforming growth factor beta1 (TGF-beta1) and procollagen type I alpha-1 (COL1A1) luciferase reporter system to investigate the possible molecular mechanism of rapid depolarization induced atrial fibrosis. Mouse atrial fibroblasts were first transfected with promoter luciferase reporters, and then cocultured with HL-1 atrial myocytes. Rapid depolarization of atrial myocytes by rapid electrical field stimulation (RES) induced increased TGF-beta1 and COL1A1 promoter activities in the cocultured atrial fibroblasts (2.4±0.3 fold of increase, p=0.008 for TGF-beta1; 2.1±0.2 fold of increase, p=0.008 for COL1A1), which were attenuated by calcium chelator BAPTA-AM and calcium channel blocker verapamil. Rapid depolarization of atrial myocytes increased paracrine secretion of angiotensin II (AngII) and reactive oxygen species (ROS) in the coculture medium. RES induced ROS generation in atrial myocytes was attenuated by membrane NADPH oxidase inhibitor apocynin. Atrial myocyte-induced TGF-beta1 and COL1A1 expressions in atrial fibroblasts were attenuated by co-treatment of AngII receptor blocker losartan and anti-oxidant N-acetylcysteine. Atrial myocyte-induced COL1A1 expression in atrial fibroblasts was attenuated by anti-TGF beta1 antibody and RNAi knockdown of TGF-beta1 receptor.
Conclusions: We first demonstrated that tachycardia of atrial myocytes induced paracrine AngII and ROS secretion, which in turn induced procollagen expression in cocultured atrial fibroblasts through increasing TGF-beta1 expression. The results of the present cellular study may have therapeutic implication that use of ARB, in combination with anti-oxidant, blocks rapid-depolarization induced atrial fibrosis.
- © 2010 by American Heart Association, Inc.