• Open Access

Repression of miR-142 by p300 and MAPK is required for survival signalling via gp130 during adaptive hypertrophy

Authors

  • Salil Sharma,

    1. Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA
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  • Jing Liu,

    1. Department of Medicine, Division of Cardiology, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA
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  • Jianqin Wei,

    1. Department of Medicine, Division of Cardiology, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA
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  • Huijun Yuan,

    1. Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA
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  • Taifang Zhang,

    1. Department of Medicine, Division of Cardiology, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA
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  • Nanette H. Bishopric

    Corresponding author
    1. Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA
    2. Department of Medicine, Division of Cardiology, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA
    • Tel: +1 305 243 6775 (office); +1 305 243 1166 (assistant); Fax: +1 305 243 9376

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Abstract

An increase in cardiac workload, ultimately resulting in hypertrophy, generates oxidative stress and therefore requires the activation of both survival and growth signal pathways. Here, we wanted to characterize the regulators, targets and mechanistic roles of miR-142, a microRNA (miRNA) negatively regulated during hypertrophy. We show that both miRNA-142-3p and -5p are repressed by serum-derived growth factors in cultured cardiac myocytes, in models of cardiac hypertrophy in vivo and in human cardiomyopathic hearts. Levels of miR-142 are inversely related to levels of acetyltransferase p300 and MAPK activity. When present, miR-142 inhibits both survival and growth pathways by directly targeting nodal regulators p300 and gp130. MiR-142 also potently represses multiple components of the NF-κB pathway, preventing cytokine-mediated NO production and blocks translation of α-actinin. Forced expression of miR-142 during hypertrophic growth induced extensive apoptosis and cardiac dysfunction; conversely, loss of miR-142 fully rescued cardiac function in a murine heart failure model. Downregulation of miR-142 is required to enable cytokine-mediated survival signalling during cardiac growth in response to haemodynamic stress and is a critical element of adaptive hypertrophy.

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