Transforming growth factor-β-mediated CD44/STAT3 signaling contributes to the development of atrial fibrosis and fibrillation

• Published in: Basic research in cardiology Vol. 112; no. 5; p. 58
• Main Authors: Chang, Shang-Hung, Yeh, Yung-Hsin, Lee, Jia-Lin, Hsu, Yu-Juei, Kuo, Chi-Tai, Chen, Wei-Jan
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2017; Springer Nature B.V
• Subjects: Animals; Atria; Atrial Fibrillation - metabolism; Atrial Fibrillation - pathology; Atrial Fibrillation - physiopathology; Atrial Fibrillation - prevention & control; Atrial Remodeling; Cardiology; CD44 antigen; Cells, Cultured; Chromatin; Collagen; Collagen Type I - genetics; Collagen Type I - metabolism; Disease Models, Animal; Fibrillation; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Fibrosis; Gene deletion; Growth factors; Heart Atria - metabolism; Heart Atria - pathology; Heart Atria - physiopathology; Heart Rate; Hyaluronan Receptors - genetics; Hyaluronan Receptors - metabolism; Hyaluronic acid; Hyaluronic Acid - metabolism; IgG antibody; Immunoglobulin G; Immunoprecipitation; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred DBA; Mice, Transgenic; Original Contribution; Pathogenesis; Plasmids; Rats, Wistar; Rhythm; Rodents; Signal Transduction; Sinus; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Stimulation; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b; Transgenic animals; Transgenic mice; Ventricle; Hyaluronan; Atrial fibrosis; Atrial fibrillation; Transforming growth factor-β; CD44
• ISSN: 0300-8428; 1435-1803; 1435-1803
• DOI: 10.1007/s00395-017-0647-9

Atrial fibrillation (AF) is associated with atrial fibrosis. Inhibition of atrial fibrosis might be a plausible approach for AF prevention and therapy. This study is designed to evaluate the potential role of CD44, a membrane receptor known to regulate fibrosis, and its related signaling in the pathogenesis of atrial fibrosis and AF. Treatment of cultured rat atrial fibroblasts with transforming growth factor-β (TGF-β, a key mediator of atrial fibrosis) led to a higher expression of hyaluronan (HA), CD44, STAT3, and collagen (a principal marker of fibrosis) than that of ventricular fibroblasts. In vivo, TGF-β transgenic mice and AF patients exhibited a greater expression of HA, CD44, STAT3, and collagen in their atria than wild-type mice and sinus rhythm subjects, respectively. Treating TGF-β transgenic mice with an anti-CD44 blocking antibody resulted in a lower expression of STAT3 and collagen in their atria than those with control IgG antibody. Programmed stimulation triggered less AF episodes in TGF-β transgenic mice treated with anti-CD44 blocking antibody than in those with control IgG. Blocking CD44 signaling with anti-CD44 antibody and mutated CD44 plasmids attenuated TGF-β-induced STAT3 activation and collagen expression in cultured atrial fibroblasts. Deletion and mutational analysis of the collagen promoter along with chromatin immunoprecipitation demonstrated that STAT3 served as a vital transcription factor in collagen expression. TGF-β-mediated HA/CD44/STAT3 pathway plays a crucial role in the development of atrial fibrosis and AF. Blocking CD44-dependent signaling may be a feasible way for AF management.