Key result
Deletion of mDia1 in mice attenuated pressure overload-induced cardiac hypertrophic responses at 3 weeks but increased the severity of heart failure at 8 weeks and mortality at 12 weeks.
Why the study?
The mechanisms by which Rho and its downstream proteins control actin dynamics during cardiac hypertrophic responses to pressure overload remain incompletely understood.
mDia1 is essential for compensatory cardiac hypertrophy during pressure overload, as its deletion attenuates hypertrophy but exacerbates heart failure and mortality.
mDia1 supports adaptive hypertrophy in pressure-overload models; leaves open its relevance as a therapeutic target in human HF.
AIMS: 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. CONCLUSION: mDia1, through actin dynamics, is involved in compensatory cardiac hypertrophy in response to pressure overload.
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Abe et al. (2020) studied Pressure overload-induced ventricular hypertrophy. mDia1 knockout vs. Wild-type mice was evaluated on Cardiac hypertrophic responses and mortality. Deletion of mDia1 in mice attenuated pressure overload-induced cardiac hypertrophic responses at 3 weeks but increased the severity of heart failure at 8 weeks and mortality at 12 weeks.
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