Disruption of Actin Dynamics Regulated by Rho Effector mDia1 Attenuates Pressure Overload-Induced Cardiac Hypertrophic Responses and Exacerbates Dysfunction.Cardiovasc Res. 2020 Jul 09 [Online ahead of print]CR
Cardiac hypertrophy is a compensatory response to pressure overload, leading to heart failure. Recent studies have demonstrated that Rho is immediately activated in left ventricles after pressure overload, and that Rho signalling plays crucial regulatory roles in actin cytoskeleton rearrangement during cardiac hypertrophic responses. However, the mechanisms by which Rho and its downstream proteins control actin dynamics during hypertrophic responses remain not fully understood. In this study, we identified the pivotal roles of mammalian homologue of Drosophila diaphanous (mDia) 1, a 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 a transverse aortic constriction (TAC) or 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 indicated that mDia1 deletion increased the severity of heart failure 8 weeks after TAC. Importantly, we could not observe apparent defects in cardiac hypertrophic responses in mDia3-knockout mice. Microarray analysis revealed that mDia1 was involved in the induction of hypertrophy related genes, including immediate early genes, in pressure overloaded hearts. Loss of mDia1 attenuated activation of the mechanotransduction pathway in TAC-operated mice hearts. We also found that mDia1 was involved in stretch-induced activation of the mechanotransduction pathway and gene expression of c-fos in neonatal rat ventricular cardiomyocytes (NRVMs). mDia1 regulated the filamentous/globular (F/G)-actin ratio in response to pressure overload in mice. Additionally, increases in nuclear myocardin-related transcription factors and serum response factor were perturbed in response to pressure overload in mDia1KO mice and to mechanical stretch in mDia1 depleted NRVMs.
mDia1, through actin dynamics, is involved in compensatory cardiac hypertrophy in response to pressure overload.
Heart disease is associated with increased cardiac mass resulting from hypertrophic growth and remodelling in response to excessive mechanical stress. Although numerous signalling pathways have been shown to influence cardiac hypertrophy, the molecular mechanisms contributing to the pressure overload-induced cardiac hypertrophy have remained incompletely understood. Here, we present evidence that the cardioprotective functions of actin polymerization by mammalian homologue of Drosophila diaphanous 1, a Rho-effector molecule, in response to mechanical stress. Understanding this mechanotransduction pathway may provide new prospects for identifying a novel strategy for pressure overload-induced cardiovascular disease.