Runx1 drives cardiac fibrosis and heart failure through epigenetic activation of myofibroblasts in pressure overload-induced cardiac remodeling.
Heart failure (HF) is often accompanied by cardiac fibrosis, a pathological process driven by activated cardiac fibroblasts (CFs) transitioning to a myofibroblast phenotype. The Runt-related transcription factor 1 (Runx1) has been implicated in various fibrotic diseases, but its role in cardiac fibrosis and HF progression remains unclear. This study aimed to elucidate the role of Runx1 in CF activation, cardiac fibrosis, and HF development.
HF was induced in mice using transverse aortic constriction (TAC). Runx1 expression was assessed in failing hearts via Western blot and qPCR, with immunostaining to localize Runx1 in CFs. In vitro, CFs were treated with TGF-β, and Runx1 knockdown was achieved using siRNA or adenoviral-mediated deletion. Myofibroblast-specific Runx1 knockout mice (PostnCre, Runx1F/F) were used to investigate the in vivo effects of Runx1 on cardiac function, fibrosis, and hypertrophy post-TAC. Chromatin immunoprecipitation (ChIP) and luciferase assays were conducted to evaluate Runx1's regulation of Postn transcription.
TAC-induced HF was associated with significant upregulation of Runx1 protein and mRNA levels, particularly in CFs. In vitro, Runx1 knockdown suppressed TGF-β-induced markers of CF activation, including α-smooth muscle actin (α-SMA), periostin (Postn), and collagen type I (Col1a1), and reduced CF migration and proliferation. PostnCre-Runx1F/F mice exhibited improved cardiac function, reduced hypertrophy, and decreased fibrosis compared to control mice post-TAC. Mechanistically, Runx1 was found to bind the Postn promoter and recruit the transcriptional coactivator P300, enhancing histone acetylation and promoting Postn transcription.
Runx1 plays a pivotal role in cardiac fibroblast activation and fibrosis, likely through epigenetic regulation of Postn expression, thereby driving heart failure progression. Targeting Runx1 may represent a promising therapeutic strategy for heart failure.
HF was induced in mice using transverse aortic constriction (TAC). Runx1 expression was assessed in failing hearts via Western blot and qPCR, with immunostaining to localize Runx1 in CFs. In vitro, CFs were treated with TGF-β, and Runx1 knockdown was achieved using siRNA or adenoviral-mediated deletion. Myofibroblast-specific Runx1 knockout mice (PostnCre, Runx1F/F) were used to investigate the in vivo effects of Runx1 on cardiac function, fibrosis, and hypertrophy post-TAC. Chromatin immunoprecipitation (ChIP) and luciferase assays were conducted to evaluate Runx1's regulation of Postn transcription.
TAC-induced HF was associated with significant upregulation of Runx1 protein and mRNA levels, particularly in CFs. In vitro, Runx1 knockdown suppressed TGF-β-induced markers of CF activation, including α-smooth muscle actin (α-SMA), periostin (Postn), and collagen type I (Col1a1), and reduced CF migration and proliferation. PostnCre-Runx1F/F mice exhibited improved cardiac function, reduced hypertrophy, and decreased fibrosis compared to control mice post-TAC. Mechanistically, Runx1 was found to bind the Postn promoter and recruit the transcriptional coactivator P300, enhancing histone acetylation and promoting Postn transcription.
Runx1 plays a pivotal role in cardiac fibroblast activation and fibrosis, likely through epigenetic regulation of Postn expression, thereby driving heart failure progression. Targeting Runx1 may represent a promising therapeutic strategy for heart failure.
Authors
An An, Zhou Zhou, Xia Xia, Wang Wang, Peng Peng, Zheng Zheng, Wang Wang, Zhang Zhang, Huang Huang, Geping Geping, Wang Wang, Zhu Zhu
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