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Transcriptome analysis of valosin-containing protein effect on cardiac hypertrophy and dysfunction

ABSTRACT: This sstudy was designed to investigate the gene netweork regulated by valosin-containing protein (VCP), an ATPase-associated protein, whic acts as a novel regulator against the cardiac stress of pressure overload. We performed transcriptome analyses to compare cardiac-specific VCP overexpression transgenic (TG) mice and wild-type (WT) mice in a series of pathological models. The left ventricular (LV) tissues were collected from both WT and VCP TG mice at 2w post TAC and at 2w post sham operations. mRNA was extracted and sequenced to generate gene expression profiles. Multiple comparisons were performed between VCP TG and WT mice at two treatment conditions: sham and 2w post TAC. Our studies revealed novel molecular mechanisms by which VCP protects heart against pressure overload-induced cardiac hypertrophy and the transition to the heart failure.

ORGANISM(S): Mus musculus

PROVIDER: GSE134085 | GEO | 2020/09/24

REPOSITORIES: GEO

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Project description: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 signaling 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 (IEGs), 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 F/G-actin ratio in response to pressure overload in mice. Additionally, 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: mDia1, through actin dynamics, is involved in compensatory cardiac hypertrophy in response to pressure overload.

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Transcriptome analysis of valosin-containing protein effect on cardiac hypertrophy and dysfunction

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