1181Role of rho-mdia1 signaling to maintain cardiac function in response to pressure overload in mice

Abstract

Abstract Background Cardiac hypertrophy is a compensatory response to pressure overload that leads to heart failure. Recent studies have shown that Rho signaling has crucial regulatory roles in actin cytoskeleton rearrangement during cardiac hypertrophic responses. Rho is rapidly activated in response to pressure overload, but the mechanisms by which Rho and its downstream proteins control actin dynamics during hypertrophic responses remain unclear. Objective To identify the essential roles of mDia1 (Rho-effector molecule) in pressure overload-induced ventricular hypertrophy. Methods and results Male wild-type (WT) and mDia1-knockout (mDia1KO) mice (10–12 weeks old) were subjected to transverse aortic constriction (TAC) or a sham operation. The heart weight/tibia length ratio, cardiomyocyte cross-sectional area, left ventricular wall thickness, and expression of hypertrophy-specific genes were significantly decreased in mDia1KO mice 3 weeks after TAC, and the mortality rate was higher at 12 weeks. Echocardiography and the pressure-volume loop indicated that mDia1 deletion increased the severity of heart failure 8 weeks after TAC. Microarray gene expression profiling showed that the induction of immediate early genes due to the TAC operation was significantly lower in mDia1KO mice than WT mice, as was the activation of extracellular signal-regulated kinase (ERK) and focal adhesion kinase (FAK). We examined the role of mDia1 in neonatal rat ventricular cardiomyocytes (NRVMs) exposed to mechanical stress. The siRNA-mediated silencing of mDia1 attenuated stretch-induced ERK and FAK phosphorylation, and gene expression of c-fos. Importantly, loss of mDia1 suppressed an increase in the F/G-actin ratio in response to pressure overload in the mice. In addition, increases in nuclear myocardin-related transcription factors (MRTFs) and serum response factor (SRF) were perturbed in response to pressure overload in mDia1KO mice and to mechanical stretch in mDia1 depleted NRVMs. Conclusions Rho-mDia1, through actin dynamics, plays critical roles in pressure overload-induced hypertrophy by regulating ERK and FAK phosphorylation and the transcriptional activity of MRTF-SRF.