Tachycardia of atrial myocytes induces collagen expression in atrial fibroblasts through transforming growth factor β1.

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 β1 (TGF-β1), connective tissue growth factor (CTGF) and procollagen type I α-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-β1, CTGF and COL1A1 promoter activities in the co-cultured atrial fibroblasts (2.4 ± 0.3-fold increase, P= 0.008 for TGF-β1; 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-β1, CTGF and COL1A1 in atrial fibroblasts was attenuated by co-treatment with the Ang II receptor blocker, losartan, and apocynin. Atrial myocyte-induced COL1A1 expression in atrial fibroblasts was attenuated by anti-TGF-β1 antibody and RNA interference knockdown of the TGF-β1 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-β1 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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Tsai CT,Tseng CD,Hwang JJ,Wu CK,Yu CC,Wang YC,Chen WP,Lai LP,Chiang FT,Lin JL

doi

10.1093/cvr/cvq322

subject

Has Abstract

pub_date

2011-03-01 00:00:00

pages

805-15

issue

4

eissn

0008-6363

issn

1755-3245

pii

cvq322

journal_volume

89

pub_type

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