IRF8 overexpression attenuated pressure overload-induced cardiac hypertrophy and fibrosis by directly interacting with and inhibiting NFATc1 signaling, whereas IRF8 deficiency aggravated pathological cardiac remodeling.
Does IRF8 suppress pathological cardiac remodelling in models of cardiac hypertrophy?
IRF8 acts as a suppressor of pathological cardiac remodelling by inhibiting calcineurin/NFATc1 signalling, highlighting it as a potential therapeutic target for cardiac hypertrophy.
p-value: p=<0.05
Interferon regulatory factor 8 (IRF8) is known to affect the innate immune response, for example, by regulating the differentiation and function of immune cells. However, whether IRF8 can influence cardiac hypertrophy is unknown. Here we show that IRF8 levels are decreased in human dilated/hypertrophic cardiomyopathic hearts and in murine hypertrophic hearts. Mice overexpressing Irf8 specifically in the heart are resistant to aortic banding (AB)-induced cardiac hypertrophy, whereas mice lacking IRF8 either globally or specifically in cardiomyocytes develop an aggravated phenotype induced by pressure overload. Mechanistically, we show that IRF8 directly interacts with NFATc1 to prevent NFATc1 translocation and thus inhibits the hypertrophic response. Inhibition of NFATc1 ameliorates the cardiac abnormalities in IRF8−/− mice after AB. In contrast, constitutive activation of NFATc1 nullifies the protective effects of IRF8 on cardiac hypertrophy in IRF8-overexpressing mice. Our results indicate that IRF8 is a potential therapeutic target in pathological cardiac hypertrophy. The transcription factor interferon regulatory factor 8 (IRF8) is known to regulate differentiation and function of immune cells. Here the authors show that IRF8 is upregulated in the hypertrophic heart in humans and mice, where it suppresses cardiac remodelling by inhibiting calcineurin signalling.
Jiang et al. (Fri,) conducted a other in Cardiac hypertrophy. IRF8 overexpression vs. Wild-type controls was evaluated on Cardiac hypertrophy and remodeling (assessed by HW/BW ratio, cardiomyocyte cross-sectional area, and fibrosis) (p=<0.05). IRF8 overexpression attenuated pressure overload-induced cardiac hypertrophy and fibrosis by directly interacting with and inhibiting NFATc1 signaling, whereas IRF8 deficiency aggravated pathological cardiac remodeling.