Cardiac fibroblast miR-27a may function as an endogenous anti-fibrotic by negatively regulating Early Growth Response Protein 3 (EGR3).

Abstract

Pathological myocardial fibrosis and hypertrophy occur due to chronic cardiac stress. The microRNA‐27a (miR‐27a) regulates collagen production across diverse cell types and organs to inhibit fibrosis and could constitute an important therapeutic avenue. However, its impact on hypertrophy and cardiac remodelling is less well‐known. We employed a transverse aortic constriction (TAC) murine model of left ventricular pressure overload to investigate the in vivo effects of genetic miR‐27a knockout, antisense inhibition of miR‐27a‐5p and fibroblast‐specific miR‐27a knockdown or overexpression. In silico Venn analysis and reporter assays were used to identify miR‐27a‐5p's targeting of Early Growth Response Protein 3 (Egr3). We evaluated the effects of miR‐27a‐5p and Egr3 upon transforming growth factor‐beta (Tgf‐β) signalling and secretome of cardiac fibroblasts in vitro. miR‐27a‐5p attenuated TAC‐induced cardiac fibrosis and myofibroblast activation in vivo, without a discernible effect on cardiac myocytes. Molecularly, miR‐27a‐5p inhibited transforming growth factor‐beta (Tgf‐β) signalling and pro‐fibrotic protein secretion in cardiac fibroblasts in vitro through suppressing the pro‐fibrotic transcription factor Early Growth Response Protein 3 (Egr3). This body of work suggests that cardiac fibroblast miR‐27a may function as an endogenous anti‐fibrotic by negatively regulating Egr3 expression.