Abstract 13233: Increased Microrna-125b In SR-A Deficient Macrophages Protects against Hypoxia/reoxygenation-Induced Cell Damage and Myocardial Ischemia/reperfusion Injury
Innate immune and inflammatory responses contribute to myocardial ischemia/reperfusion (I/R) injury. The macrophage scavenger receptor class A (SR-A) participates in the innate immune response. We have reported that macrophage SR-A plays a role in endotoxin-activated TLR4-mediated NF-κB signaling. SR-A mainly expresses on macrophages. We hypothesized that macrophage SR-A plays a role in hypoxia/reoxygenation (H/R)-induced cell injury. To test our hypothesis, we isolated peritoneal macrophages from SR-A deficient (SR-A-/-) and wild type (WT) mice. Macrophages (n=6/group) were subjected to hypoxia (2 h) followed by reoxygenation. H/R markedly increased NF-κB binding activity and KC and MCP-1 production in WT macrophages but not in SR-A-/- macrophages. H/R-increased caspase-3 and -8 activities and decreased cell viability were significantly attenuated in SR-A-/- macrophages. qPCR showed that the levels of microRNA-125b (miR-125b) in SR-A-/- macrophages were greater than that in WT macrophages. Hypoxia further increased expression of miR-125b in SR-A-/- macrophages but not in WT macrophages. To determine the role of miR-125b in H/R-induced cell injury, we transfected WT macrophages with miR-125b mimics (n=6). Scrambled mimics served as control mimics (n=6). H/R-induced caspase-3 and-8, LDH activity, and decreased cell viability were significantly attenuated by transfection of miR-125b mimics. miR-125b mimics suppressed p-53 and Bak-1 expression and prevented H/R-increased Bax levels in macrophages. To investigate the role of miR-125b in SR-A-/- macrophages in myocardial I/R injury, we induced myocardial ischemia (60 min) followed by reperfusion up to 7 days in SR-A-/- and WT mice (n=8/group). qPCR showed that the levels of miR-125b were increased by 70% in SR-A-/- I/R mice compared with WT I/R mice. SR-A-/- mice showed significant attenuation of I/R-decreased cardiac function. Myocardial infarct size in SR-A-/- mice was markedly smaller than that in WT mice. I/R-increased myocardial apoptosis and activated p53-mediated Bak-1 apoptotic signaling were markedly attenuated by SR-A deficiency. We conclude that macrophage miR-125b plays a protective role in myocardial I/R injury via targeting p53-mediated Bak-1 apoptotic signaling.
- © 2012 by American Heart Association, Inc.