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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Ren, Danyang¹  Wang, Xiaohui¹  Ha, Tuanzhu¹  Liu, Li²  Kalbfleisch, John³  Gao, Xiang⁴  Williams, David¹  Li, Chuanfu¹ 

[1] E Tennessee State Univ, Dept Surg, Johnson City, TN 37614 USA

[2] Nanjing Med Univ, Affiliated Hosp 1, Dept Geriatr, Nanjing 210029, Jiangsu, Peoples R China

[3] E Tennessee State Univ, Dept Biometry & Med Comp, Johnson City, TN 37614 USA

[4] Nanjing Univ, Anim Model Res Ctr, Nanjing 210093, Jiangsu, Peoples R China

关键词: microRNA-125b;    Macrophage SR-A;    Hypoxia/reoxygenation;    Myocardial I/R injury;    Apoptosis;   

DOI  :  10.1016/j.bbadis.2012.10.012

来源: Elsevier

【 摘 要 】

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 (45 min) followed by reperfusion for up to 7 days. 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-kappa B 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. (C) 2012 Elsevier B.V. All rights reserved.

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