Gelsolin is an important mediator of Angiotensin II-induced activation of cardiac fibroblasts and fibrosis.

Abstract

Myocardial fibrosis is a characteristic of various cardiomyopathies, and myocardial fibroblasts play a central role in this process. Gelsolin (GSN) is an actin severing and capping protein that regulates actin assembly and may be involved in fibroblast activation. While the role of GSN in mechanical stress-mediated cardiac fibrosis has been explored, its role in myocardial fibrosis in the absence of mechanical stress is not defined. In this study, we investigated the role of GSN in myocardial fibrosis induced by Angiotensin II (Ang II), a profibrotic hormone that is elevated in cardiovascular disease. We utilized mice lacking GSN (Gsn-/- ) and cultured primary adult cardiac fibroblasts (cFB). In vivo, Ang II infusion in mice resulted in significantly less severe myocardial fibrosis in Gsn-/- compared with Gsn+/+ mice, along with diminished activation of the TGFβ1-Smad2/3 pathway, and reduced expression of cardiac extracellular matrix proteins (collagen, fibronectin, periostin). Moreover, Gsn-deficient hearts exhibited suppressed activity of the AMPK pathway and its downstream effectors, mTOR and P70S6Kinase, which could contribute to the suppressed TGFβ1 activity. In vitro, the Ang II-induced activation of cFBs was reduced in Gsn-deficient fibroblasts evident from decreased expression of αSMA and periostin, diminished actin filament turnover; which also exhibited reduced activity of the AMPK-mTOR pathway, and P70S6K phosphorylation. AMPK inhibition compensated for the loss of GSN, restored the levels of G-actin in Gsn-/- cFBs and promoted activation to myofibroblasts by increasing αSMA and periostin levels. This study reveals a novel role for GSN in mediating myocardial fibrosis by regulating the AMPK-mTOR-P70S6K pathway in cFB activation independent from mechanical stress-induced factors.