Autophagy is a regulator of TGF-β1-induced fibrogenesis in primary human atrial myofibroblasts

Abstract

Transforming growth factor-β1 (TGF-β1) is an important regulator of fibrogenesis in heart disease. In many other cellular systems, TGF-β1 may also induce autophagy, but a link between its fibrogenic and autophagic effects is unknown. Thus we tested whether or not TGF-β1-induced autophagy has a regulatory function on fibrosis in human atrial myofibroblasts (hATMyofbs). Primary hATMyofbs were treated with TGF-β1 to assess for fibrogenic and autophagic responses. Using immunoblotting, immunofluorescence and transmission electron microscopic analyses, we found that TGF-β1 promoted collagen type Iα2 and fibronectin synthesis in hATMyofbs and that this was paralleled by an increase in autophagic activation in these cells. Pharmacological inhibition of autophagy by bafilomycin-A1 and 3-methyladenine decreased the fibrotic response in hATMyofb cells. ATG7 knockdown in hATMyofbs and ATG5 knockout (mouse embryonic fibroblast) fibroblasts decreased the fibrotic effect of TGF-β1 in experimental versus control cells. Furthermore, using a coronary artery ligation model of myocardial infarction in rats, we observed increases in the levels of protein markers of fibrosis, autophagy and Smad2 phosphorylation in whole scar tissue lysates. Immunohistochemistry for LC3β indicated the localization of punctate LC3β with vimentin (a mesenchymal-derived cell marker), ED-A fibronectin and phosphorylated Smad2. These results support the hypothesis that TGF-β1-induced autophagy is required for the fibrogenic response in hATMyofbs.

Autophagy Improves the Immunosuppression of CD4+ T Cells by Mesenchymal Stem Cells Through Transforming Growth Factor-β1

“…Among these members, TGF-b1 is the predominate isoform of this family that is expressed in the immune system [20] and that is responsible for MSC-mediated inhibition of T cells [21]. Some studies demonstrated that TGF-b could activate the autophagy [22], whereas some other studies showed that autophagy could regulate the TGF-b expression of some cells [23,24].…”

Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction

“…57 Furthermore, in TGFB1-treated primary human atrial myofibroblasts, autophagy was required for the induction of fibrotic signaling and the synthesis of both COL1A2 and FN1. 22 These interesting findings not only suggest a connection between autophagy and the synthesis of secretory proteins under certain stress conditions, but also raise 3 important questions that need to be addressed by further studies: 1. How possibly can the catabolic machinery of autophagy participate in an anabolic process of protein synthesis?…”

“…Intriguingly, depending on the cell or tissue type and pathological settings, autophagy can be profibrotic or antifibrotic in these organs. [22][23][24][25] For example, autophagy induced in hepatic stellate cells can break down lipids to fuel the activation of these cells to promote liver fibrosis. 26,27 In contrast, autophagy in hepatic macrophages and hepatocytes inhibits inflammation and apoptosis, resulting in the prevention of liver fibrosis.…”

Aspirin alleviates cardiac fibrosis in mice by inhibiting autophagy

“…The importance of autophagy in cardiac fibrosis was realized recently, when many reports suggested that autophagy is required for the fibrosis response [25,28,29] , although the role of ASA on CF autophagy is not clear. In this study, we found that ASA performed its anti-fibrotic function at least partly It has been reported that an increase in ROS levels is accompanied by p38 activation, fibrosis, apoptosis and cardiac dys- [18,30] .…”