Tachycardia of Atrial Myocytes Induces Collagen Expression in Atrial Fibroblasts through Transforming Growth Factor Beta1
Resource
CARDIOVASCULAR RESEARCH v.89 n.4 pp.805-815
Journal
CARDIOVASCULAR RESEARCH
Journal Volume
v.89
Journal Issue
n.4
Pages
805-815
Date Issued
2011
Date
2011
Author(s)
TSAI, CHIA-TI
TSENG, CHUEN-DEN
HWANG, JUEY-JEN
WU, CHO-KAI
YU, CHIH-CHIEH
WANG, YI-CHIH
CHEN, WEN-PIN
LAI, LING-PING
CHIANG, FU-TIEN
LIN, JIUNN-LEE
Abstract
AIMS: We investigated the molecular mechanism of rapid- depolarization- induced atrial fibrosis. METHODS AND RESULTS: We used a direct atrial myocyte-fibroblast contact co- culture and a fibroblast-specific transforming growth factor 1 (TGF- 1), connective tissue growth factor ( CTGF) and procollagen type I -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 co-cultured with HL-1 atrial myocytes. Rapid depolarization of atrial myocytes by rapid electrical field stimulation induced increased TGF- 1, CTGF and COL1A1 promoter activities in the co-cultured atrial fibroblasts ( 2.4 0.3-fold increase, P= 0.008 for TGF- 1; 2.9 0.4- fold increase, P< 0.001 for CTGF; and 2.1 0.2-fold increase, P= 0.008 for COL1A1). Rapid depolarization of atrial myocytes increased paracrine secretion of angiotensin II (Ang II) and reactive oxygen species in the co-culture medium. Rapid electrical field stimulation-induced ROS generation in atrial myocytes was attenuated by the membrane NADPH oxidase inhibitor, apocynin. Atrial myocyte-induced expression of TGF- 1, CTGF and COL1A1 in atrial fibroblasts was attenuated by co-treatment with the Ang II receptor blocker, losartan, and apocynin. Atrial myocyte-induced COL1 A1 expression in atrial fibroblasts was attenuated by anti- TGF- 1 antibody and RNA interference knockdown of the TGF- 1 receptor. CONCLUSION: We first demonstrated that tachycardia of atrial myocytes induced paracrine secretion of Ang II and reactive oxygen species, which in turn induced expression of CTGF and procollagen in co-cultured atrial fibroblasts through increasing TGF- 1 expression. The results may imply that use of an Ang II receptor blocker, in combination with an anti-oxidant, blocks rapid- depolarization-induced atrial fibrosis.
Subjects
Rapid depolarization
Atrial fibrillation
Procollagen
Transforming growth factor
Angiotensin II
Reactive oxygen species
Contact co-culture