Abstract 17903: Cardioprotection by Exogenously Administered Endothelial Progenitor Cells (EPCs) After Ischemia-Reperfusion Injury is eNOS Dependent
Background: Nitric oxide (NO) production from eNOS protects cardiomyocytes from apoptosis after ischemia-reperfusion (IR) injury. Recent studies suggest that exogenously administered endothelial progenitor cells (EPCs) preserve cardiac function after myocardial infarction both in animals and humans. This study was performed to test whether EPC-mediated cardioprotection is dependent on EPC eNOS expression.
Methods and Results: Eight- to 10-week-old C57BL6 wild-type (WT) mice underwent cardiac IR injury (60 min-LAD occlusion followed by reperfusion). ELISA and FACS analysis revealed an increase in eNOS expression in bone marrow (BM) followed by EPC mobilization after IR. To determine whether upregulation of eNOS in BM is essential for EPC mobilization, we induced IR injury in WT mice transplanted with BM from eNOS-KO mice (WT/KOBM) and in eNOS-KO mice transplanted with WT BM (KO/WTBM). Augmentation of EPC mobilization was observed in KO/WTBM mice, but not in WT/KOBM mice. Notably, a decrease in cardiomyocytes apoptosis in the area at risk (AAR) and reduced infarct size were observed in KO/WTBM mice vs. WT/KOBM mice 3 days after IR. To determine whether eNOS expression in circulating EPCs is essential for cardioprotection after IR injury, we preformed IR injury on splenectomized WT mice and administered DiI-labeled 4 day-cultured EPCs (5 × 105) from either WT mouse BM or eNOS-KO mouse BM, or saline via IV infusion 1 day after IR. 3 days after IR, significantly less apoptosis in AAR and smaller infarction were observed in WT EPC group but not in eNOS-KO EPC group compared to saline group. Interestingly, incorporation of EPCs into AAR was similar in both EPC group. Moreover, echocardiography showed that fractional shortening was significantly preserved in WT EPC group, but not in eNOS-KO EPC group than saline group 2 and 4 weeks after IR.
Conclusions: Our data indicate that EPC eNOS expression is required for EPC mediated anti-apoptotic effects and preservation of LV function after myocardial infarction via mechanisms that are independent of EPC incorporation into the ischemic area. Our findings suggest that, in addition to the importance of eNOS for BM mobilization, eNOS expression by recruited EPCs plays a key role in myocardial protection.
- © 2010 by American Heart Association, Inc.