Abstract 10504: SR-A Deficiency Protects the Myocardium From Ischemic Injury: Involving Upregulation of Mir-125b and Mir- 146a Expression
The innate immune response is involved in myocardial ischemia/reperfusion (I/R) injury. The macrophage scavenger receptor class A (SR-A) plays a role in the induction of innate immune responses. We hypothesized that SR-A contributes to myocardial I/R injury. To evaluate our hypothesis, we induced myocardial ischemia (60 min) followed by reperfusion (4 hrs) in SR-A deficient (SR-A-/-, n=10) and wild type (WT) mice (n=9). Infarct size was assessed by TTC staining and cardiac myocyte apoptosis was evaluated by the TUNEL assay. Cardiac function (n=6) was examined 3 and 7 days after myocardial I/R by echocardiography. Infarct size was reduced by 37.8% and fractional shortening (%FS) and ejection fraction (EF) were significantly improved at 3 and 7 days after myocardial I/R in SR-A-/- mice compared with WT I/R mice. SR-A deficiency attenuated I/R-induced cardiac myocyte apoptosis, prevented I/R-increased Fas, FasL, and caspase-3 activity, blunted I/R-induced IRAK phosphorylation and NF-κB activation in the myocardium. To determine the mechanisms by which SR-A deficiency attenuated myocardial ischemic injury, we examined the levels of 12 different miRs in heart tissues by real time PCR. miR-125b and miR-146a levels were significantly increased in SR-A-/- I/R mice, but not in WT I/R mice, compared with sham controls. We transfected WT mouse hearts with lentivirus expressing miR125b (LmiR-125b) and LmiR-146a, respectively. Lentivirus vector served as control. Seven days after transfection, the hearts were subjected to I/R. Infarct size (n=6/group) was examined. Cardiac function (n=6/group) was measured at 3 and 7 days after myocardial I/R. LmiR-125b transfection reduced infarct size by 41% and significantly attenuated I/R-decreased EF% and %FS compared with I/R control. Similar results were observed in LmiR-146a transfection. Lentivirus vector transfection alone did not alter I/R-induced infarction. Western blot showed that LmiR-125b targeted p53-mediated Fas/FasL apoptotic signaling and LmiR-146a targeted IRAK/TRAF6-mediated NF-κB activation pathway. We conclude that SR-A deficiency protects against myocardial ischemic injury via upregulating expression of miR-125b and miR-146a which attenuated I/R-induced apoptosis and NF-κB activation.
- © 2011 by American Heart Association, Inc.