SR-A Deficiency Reduces Myocardial Ischemia/Reperfusion Injury; Involvement of Increased microRNA-125b Expression in Macrophages
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.
Ren, Danyang; Wang, Xiaohui; Ha, Tuanzhu; Liu, Li; Kalbfleisch, John; Gao, Xiang; Williams, David; and Li, Chuanfu. 2013. SR-A Deficiency Reduces Myocardial Ischemia/Reperfusion Injury; Involvement of Increased microRNA-125b Expression in Macrophages. Biochimica et Biophysica Acta - Molecular Basis of Disease. Vol.1832(2). 336-346. https://doi.org/10.1016/j.bbadis.2012.10.012 PMID: 23123599 ISSN: 0925-4439