title: SR-A deficiency reduces myocardial ischemia/reperfusion injury; involvement of increased microRNA-125b expression in macrophages.
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.
authors.affiliation: Department of Surgery, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Danyang
authors.initials: D
authors.lastname: Ren
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: John
authors.initials: J
authors.lastname: Kalbfleisch
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D015428:Myocardial Reperfusion Injury / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000502:physiology*
chemical_list: C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D051117:Scavenger Receptors, Class A