MicroRNA‐378 inhibition promotes angiotensin II induced cardiac hypertrophy and fibrosis: role of paracrine signaling from cardiomyocytes to cardiac fibroblasts (868.1)

Abstract

MicroRNAs play significant roles in cardiac remodeling during heart failure. We have recently shown that miR‐378 is mainly expressed in cardiac myocytes (JBC 2012;287(16):12913‐26) and its over‐expression counteracts cardiac hypertrophy (JBC 2013;288(16):11216‐32). Intriguingly, whole body knockout of miR‐378 has also shown benefits against high fat diet induced obesity. However, cardiac effects of miR‐378 deficiency remain unknown. We examined cardiac response of miR‐378 depletion in mice 7 days following 3 consecutive injections (70 mg/kg, i.p.) of LNA‐ modified 378‐antimiR. We found induction of hypertrophy markers and fibrotic gene expression, and de‐repression of targets, IGF1R and Grb‐2. Ang‐II‐induced cardiac dysfunction and remodeling was drastically enhanced by 378‐antimiR treatment. Inhibition of miR‐378 alone led to induction of TGFβ1 expression in mouse hearts. It stimulated TGFβ1 promoter activity via inducing AP‐1 transcriptional activity and Ras‐signaling. Conditioned medium (CM) of miR‐378 depleted cardiomyocytes resulted in cardiac fibroblast cell differentiation with enhanced fibronectin (FN) and collagen (Col1) expression, which was blocked by inclusion of TGFβ1‐neutralizing antibody in the CM. MiR‐378 over‐expressing cardiomyocytes were found to secrete miR‐378 in the culture medium. The secreted miR‐378 was effectively taken up by cardiac fibroblasts where it repressed AngII‐stimulated FN and Col1 expression. Our findings disclose a new paracrine role of cardiac myocytes in the control of fibroblast cell differentiation involving miR‐378. Our data demonstrate that miR‐378 inhibition promotes adverse ventricular remodeling. Thus, previously suggested therapeutic targeting of miR‐378 in metabolic disorders should be exercised cautiously as it could have deleterious cardiac consequences particularly in conditions of preexisting cardiac disorders.Grant Funding Source: NIH/NHLBI 5R01HL022231‐35