Tachycardia of atrial myocytes induces collagen expression in atrial fibroblasts through transforming growth factor β1.
OBJECTIVE
We investigated the molecular mechanism of rapid-depolarization-induced atrial fibrosis.


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.


CONCLUSIONS
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.
Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, No. 1, Section 1, Jen-Ai Road, Taipei 100, Taiwan.
Chia-Ti
CT
Tsai
Chuen-Den
CD
Tseng
Juey-Jen
JJ
Hwang
Cho-Kai
CK
Wu
Chih-Chieh
CC
Yu
Yi-Chih
YC
Wang
Wen-Pin
WP
Chen
Ling-Ping
LP
Lai
Fu-Tien
FT
Chiang
Jiunn-Lee
JL
Lin
D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D002450:Cell Communication; D002478:Cells, Cultured; D018920:Coculture Techniques; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor / Q000235:genetics; D004558:Electric Stimulation; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D006325:Heart Atria / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D019255:NADPH Oxidases / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013610:Tachycardia / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
C000716128:Col1a1 protein, mouse; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D019255:NADPH Oxidases