SR-A deficiency reduces myocardial ischemia/reperfusion injury; involvement of increased microRNA-125b expression in macrophages

Biochim Biophys Acta. 2013 Feb;1832(2):336-46. doi: 10.1016/j.bbadis.2012.10.012. Epub 2012 Oct 30.

Abstract

The macrophage scavenger receptor class A (SR-A) participates in the innate immune and inflammatory responses. This study examined the role of macrophage SR-A in myocardial ischemia/reperfusion (I/R) injury and hypoxia/reoxygenation (H/R)-induced cell damage. SR-A(-/-) and WT mice were subjected to ischemia (45min) followed by reperfusion for up to 7days. SR-A(-/-) mice showed smaller myocardial infarct size and better cardiac function than did WT I/R mice. SR-A deficiency attenuated I/R-induced myocardial apoptosis by preventing p53-mediated Bak-1 apoptotic signaling. The levels of microRNA-125b in SR-A(-/-) heart were significantly greater than in WT myocardium. SR-A is predominantly expressed on macrophages. To investigate the role of SR-A macrophages in H/R-induced injury, we isolated peritoneal macrophages from SR-A deficient (SR-A(-/-)) and wild type (WT) mice. Macrophages were subjected to hypoxia followed by reoxygenation. H/R markedly increased NF-κB binding activity as well as KC and MCP-1 production in WT macrophages but not in SR-A(-/-) macrophages. H/R induced caspase-3/7 and -8 activities and cell death in WT macrophages, but not in SR-A(-/-) macrophages. The levels of miR-125b in SR-A(-/-) macrophages were significantly higher than in WT macrophages. Transfection of WT macrophages with miR-125b mimics attenuated H/R-induced caspase-3/7 and -8 activities and H/R-decreased viability, and prevented H/R-increased p-53, Bak-1 and Bax expression. The data suggest that SR-A deficiency attenuates myocardial I/R injury by targeting p53-mediated apoptotic signaling. SR-A(-/-) macrophages contain high levels of miR-125b which may play a role in the protective effect of SR-A deficiency on myocardial I/R injury and H/R-induced cell damage.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Enzyme-Linked Immunosorbent Assay
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / genetics*
  • Myocardial Reperfusion Injury / genetics*
  • Real-Time Polymerase Chain Reaction
  • Scavenger Receptors, Class A / genetics
  • Scavenger Receptors, Class A / physiology*

Substances

  • MIRN125 microRNA, human
  • MicroRNAs
  • Scavenger Receptors, Class A