HDL protects against myocardial ischemia reperfusion injury via miR-34b and miR-337 expression which requires STAT3

PLoS One. 2019 Jun 20;14(6):e0218432. doi: 10.1371/journal.pone.0218432. eCollection 2019.

Abstract

Purpose: High density lipoprotein (HDL) protects against myocardial infarction via mechanisms that remain unclear. STAT3 (signal transducer and activator of transcription 3) plays a key role in HDL-induced cardioprotection. In the heart, microRNAs (miRNAs) are involved in ischemia reperfusion injury. We therefore investigated whether the cardioprotective effect of HDL modulates miRNAs as a downstream target of STAT3 activation.

Methods: STAT3 cardiomyocyte deficient mice (STAT3-KO) and wildtype littermates (STAT3-WT) were submitted to left coronary ligature and reperfused (IR) with or without injection of HDL. Infarct size (IS) was determined and cardiac miRNA expression was evaluated after reperfusion in sham, IR and IR+HDL hearts by microarray analysis. In vitro, neonatal rat ventricular cardiomyocytes were submitted to hypoxia with or without HDL incubation. Cell viability and miRNA expression were analysed.

Results: In vivo, HDL reduced IS from 40.5±4.3% to 24.4±2.1% (p<0.05) in STAT3-WT mice. HDL failed to protect in STAT3-KO mice. In STAT3-WT mice, both miR-34b and miR-337 were increased in IR compared to sham and IR+HDL groups (p<0.05). These miRNAs were not modulated in STAT3-KO mice. In vitro, incubation with HDL improved cell viability against hypoxia (p<0.05). The expression of miR-34b and miR-337 was increased by hypoxia and reduced by HDL treatment (p<0.05). In cardiomyocytes transfected with miRNA mimics, HDL failed to improve cell viability against hypoxia.

Conclusions: Our study, performed both in vivo and in vitro, delineates a novel cardioprotective signalling pathway activated by HDL, involving STAT3-mediated decrease of miR-34b and miR-337 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Survival / drug effects
  • Humans
  • Lipoproteins, HDL / metabolism
  • Lipoproteins, HDL / pharmacology
  • Mice
  • MicroRNAs / genetics*
  • Myocardial Reperfusion Injury / drug therapy*
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / pathology
  • Phosphorylation / drug effects
  • Rats
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction / drug effects

Substances

  • Lipoproteins, HDL
  • MIRN337 microRNA, rat
  • MIRN34 microRNA, rat
  • MIRN34a microRNA, mouse
  • MicroRNAs
  • STAT3 Transcription Factor

Grant support

The present study was supported by the Swiss National Science Foundation (SNSF grant 31-135221 to R.W.J. and SNSF grant 310030_152639 to F.M.) and Fondation Prévot, Jubiläumsstiftung SwissLife and Fondation pour la lutte contre le cancer et investigations médico-biologiques (M.A.F.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.