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

Salil Sharma, Jing Liu, Jianqin Wei, Huijun Yuan, Taifang Zhang, Nanette Bishopric

Research output: Contribution to journalArticle

55 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)617-632
Number of pages16
JournalEMBO Molecular Medicine
Volume4
Issue number7
DOIs
StatePublished - Jul 1 2012

Fingerprint

Hypertrophy
Survival
Growth
MicroRNAs
Cytokines
Actinin
Cardiomegaly
Workload
Cardiac Myocytes
Signal Transduction
Intercellular Signaling Peptides and Proteins
Oxidative Stress
Down-Regulation
Heart Failure
Hemodynamics
Apoptosis
Serum

Keywords

  • Apoptosis
  • Epigenetics
  • Hypertrophy
  • IL6st
  • Nitric oxide

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Repression of miR-142 by p300 and MAPK is required for survival signalling via gp130 during adaptive hypertrophy. / Sharma, Salil; Liu, Jing; Wei, Jianqin; Yuan, Huijun; Zhang, Taifang; Bishopric, Nanette.

In: EMBO Molecular Medicine, Vol. 4, No. 7, 01.07.2012, p. 617-632.

Research output: Contribution to journalArticle

Sharma, Salil ; Liu, Jing ; Wei, Jianqin ; Yuan, Huijun ; Zhang, Taifang ; Bishopric, Nanette. / Repression of miR-142 by p300 and MAPK is required for survival signalling via gp130 during adaptive hypertrophy. In: EMBO Molecular Medicine. 2012 ; Vol. 4, No. 7. pp. 617-632.
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