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Actin-related protein 5 suppresses the cooperative activation of cardiac gene transcription by myocardin and MEF2.

ABSTRACT: MYOCD is a transcription factor important for cardiac and smooth muscle development. We previously identified that actin-related protein 5 (ARP5) binds to the N-terminus of MYOCD. Here, we demonstrate that ARP5 inhibits the cooperative action of the cardiac-specific isoform of MYOCD with MEF2. ARP5 overexpression in murine hearts induced cardiac hypertrophy and fibrosis, whereas ARP5 knockdown in P19CL6 cells significantly increased cardiac gene expression. ARP5 was found to bind to a MEF2-binding motif of cardiac MYOCD and inhibit MEF2-mediated transactivation by MYOCD. RNA-seq analysis revealed 849 genes that are upregulated by MYOCD-MEF2 and 650 genes that are repressed by ARP5. ARP5 expression increased with cardiomyopathy and was negatively correlated with the expression of Tnnt2 and Ttn, which were regulated by cardiac MYOCD-MEF2. Overall, our data suggest that ARP5 is a potential suppressor of cardiac MYOCD during physiological and pathological processes.

SUBMITTER: Morita T

PROVIDER: S-EPMC9900090 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Actin-related protein 5 suppresses the cooperative activation of cardiac gene transcription by myocardin and MEF2.

Morita Tsuyoshi T Hayashi Ken'ichiro K

FEBS open bio 20230112 2

MYOCD is a transcription factor important for cardiac and smooth muscle development. We previously identified that actin-related protein 5 (ARP5) binds to the N-terminus of MYOCD. Here, we demonstrate that ARP5 inhibits the cooperative action of the cardiac-specific isoform of MYOCD with MEF2. ARP5 overexpression in murine hearts induced cardiac hypertrophy and fibrosis, whereas ARP5 knockdown in P19CL6 cells significantly increased cardiac gene expression. ARP5 was found to bind to a MEF2-bindi ...[more]

PMID: 36610028

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Project description:Activation of hepatic stellate cells (HSCs), characterized by development of a robust actin cytoskeleton and expression of abundant extracellular matrix (ECM) proteins, such as type 1 collagen (COL.1), is a central cellular and molecular event in liver fibrosis. It has been demonstrated that HSCs express both myocardin and myocardin-related transcription factor-A (MRTF-A). However, the biological effects of myocardin and MRTF-A on HSC activation and liver fibrosis, as well as the molecular mechanism under the process, remain unclear. Here, we report that myocardin and MRTF-A's expression and nuclear accumulation are prominently increased during the HSC activation process, accompanied by robust activation of actin cytoskeleton dynamics. Targeting myocardin and MRTF-A binding and function with a novel small molecule, CCG-203971, led to dose-dependent inhibition of HSC actin cytoskeleton dynamics and abrogated multiple functional features of HSC activation (i.e., HSC contraction, migration and proliferation) and decreased COL.1 expression in vitro and liver fibrosis in vivo. Mechanistically, blocking the myocardin and MRTF-A nuclear translocation pathway with CCG-203971 directly inhibited myocardin/MRTF-A-mediated serum response factor (SRF), and Smad2/3 activation in the COL.1α2 promoter and indirectly abrogated actin cytoskeleton-dependent regulation of Smad2/3 and Erk1/2 phosphorylation and their nuclear accumulation. Finally, there was no effect of CCG-203971 on markers of inflammation, suggesting a direct effect of the compound on HSCs and liver fibrosis. These data reveal that myocardin and MRTF-A are two important cotranscriptional factors in HSCs and represent entirely novel therapeutic pathways that might be targeted to treat liver fibrosis.NEW & NOTEWORTHY Myocardin and myocardin-related transcription factor-A (MRTF-A) are upregulated in activated hepatic stellate cells (HSCs) in vitro and in vivo, closely associated with robustly increased actin cytoskeleton remodeling. Targeting myocardin and MRTF-A by CCG-203971 leads to actin cytoskeleton-dependent inhibition of HSC activation, reduced cell contractility, impeded cell migration and proliferation, and decreased COL.1 expression in vitro and in vivo. Dual expression of myocardin and MRTF-A in HSCs may represent novel therapeutic targets in liver fibrosis.

Dataset Information

Actin-related protein 5 suppresses the cooperative activation of cardiac gene transcription by myocardin and MEF2.

Publications

Actin-related protein 5 suppresses the cooperative activation of cardiac gene transcription by myocardin and MEF2.

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