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Atorvastatin At Reperfusion Reduces Myocardial Infarct Size In Mice By Activating eNOS Of Bone Marrow-derived Cells
Zequan Yang1, Gorav Ailawadi1, Joel Linden2, Brent A. French3, Irving L. Kron1; 1Surgery, University of Virginia Health System, Charlottesville, VA; 2Medicine, University of Virginia Health System, Charlottesville, VA; 3Biomedical Engineering, University of Virginia Health System, Charlottesville, VA
READER COMMENTS
Objective: Myocardial injury occurs after cardiac surgery despite optimal myocardial protective strategy. Recently, clinical and experimental studies indicate that the advantage of early statin use after acute coronary syndromes is independent of baseline levels of cholesterol. We hypothesized that atorvastatin could reduce infarct size in intact mice by activation of eNOS, specifically the eNOS on bone marrow-derived cells.
Methods: C57BL/6J mice (B6) and congenic eNOS knockout (KO) mice underwent 45 min LAD occlusion and 60 min reperfusion. Chimeric mice, created by bone marrow transplantation to post-irradiation mice between B6 and eNOS KO mice, underwent 40 min LAD occlusion and 60 min reperfusion. Mice were treated either with vehicle or atorvastatin in 5% ethanol at a dose of 10mg/kg IV 5 min before initiating reperfusion. Infarct size was evaluated by TTC and Phthalo blue staining.
Results: In B6 and eNOS KO mice, risk regions (RR, % of LV mass) were comparable among the four study groups. In vehicle-control B6 mice, post-ischemic reperfusion resulted in an infarct size of 62±2% of RR. Atorvastatin treatment caused a 19% decrease in infarct size in B6 mice (vs. vehicle control, p<0.05). In eNOS KO vehicle-control mice, infarct size was comparable to that of B6 vehicle-control mice (65±2 vs. 62±2%, p=NS). Atorvastatin treatment had no effect on infarct size in eNOS KO mice (vs. eNOS KO vehicle-control, p=NS). In chimeras, Atorvastatin significantly reduced infarct size in B6/B6 (donor/recipient) mice and B6/KO mice, but not in KO/KO mice or KO/B6 mice (see figure).
Conclusion: The results demonstrate that acute administration of atorvastatin significantly reduces myocardial ischemia/reperfusion injury in an eNOS-dependent manner, probably through the post-transcriptional activation of eNOS in bone marrow-derived cells. The results support further clinical study to test the role of acute administration of Atorvastatin in patients undergoing cardiac surgery, even in the absence of coronary artery disease.

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