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Myocardial infarction (MI)-induced cardiac remodeling includes chamber dilatation, contractile dysfunction, and fibrosis. Of these, fibrosis is the least understood. After MI, activated cardiac fibroblasts deposit extracellular matrix, leading to pathological myocardial fibrosis. Current therapies to prevent cardiac fibrosis are still unavailable and novel therapeutic targets are extremely needed.
MI models were induced by permanent ligation of coronary artery in male C57bl6J mice. Primary cardiac fibroblasts were isolated from Sham or MI-operated murine hearts. Cardiac fibroblast specific SWELL1 knockdown was induced by in vivo intra-myocardial injection of adeno-associated virus phenotype 9 (AAV9) which carries Col1α2-SWELL1 shRNA. Ventricular function and structure were respectively evaluated by echocardiography and masson trichrome staining at 4 weeks post-MI.
Herein we report that SWELL1 (LRRC8a), a member of the Leucine-Rich Repeat Containing protein family, is an essential component of a volume-sensitive ion channel (VSIC) in murine cardiac fibroblasts. We find that SWELL1-induced VSIC was obviously augmented in cardiac fibroblasts isolated from murine failing hearts following MI. By using intra-myocardial AAV9 injection, we successfully generated cardiac fibroblast-specific SWELL1 knockdown mouse models. We show that knockdown of SWELL1 expression in cardiac fibroblasts markedly ameliorated fibrogenesis, left ventricular dysfunction, and excessive scarring in the post-MI heart. Down-regulation of SWELL1 inhibited the profibrotic myofibroblast phenotype in both isolated cardiac fibroblasts and in post-MI hearts. Mechanistically, SWELL1 obviously promoted profibrotic TGF-ß/Smad3 signaling activation via directly interactions with Smad3. Furthermore, silencing of SWELL1 caused the significant decrease of Smad3 transcriptional activity. This signaling pathway is crucial to the pathologies because over-expression of Smad3 markedly exacerbated cardiac fibrosis and promoted ventricular dysfunction in SWELL1-knockdown hearts post-MI.
These results for the first time support targeting SWELL1 in cardiac fibrotic diseases and establish critical roles of cardiac fibroblasts in remodeling and ventricular dysfunction following MI.