Abstract 12246: Activation of Hypoxia Inducible Factor-Erythropoietin Pathway May Prevent Acute Myocardial Injury During Remote Ischemic Preconditioning
Background: Remote ischemic preconditioning (RIPC) has cardiac protective effects. However, the mechanism underlying RIPC remains unknown. Similarly, many lines of evidence suggest that erythropoietin has cardioprotective roles, but little is known regarding the role of erythropoietin in cardioprotection during RIPC. We investigated whether erythropoietin would be induced during RIPC, and whether this would contribute to preventing acute myocardial injury.
Methods and Results: We measured plasma levels of erythropoietin before and after RIPC in healthy volunteers (n=10). RIPC was induced with an automated blood pressure cuff inflated to 200 mm Hg on the right upper limb. RIPC comprised three episodes of 5-min ischemia followed by a 5-min cuff deflation for reperfusion. We found that erythropoietin was significantly increased at 24 h after RIPC (p<0.01). Next, we examined erythropoietin expression in mouse kidney after RIPC (n=5). RIPC comprised three cycles of 5 min occlusion and 5 min reperfusion of the right femoral artery. Real-time PCR revealed that erythropoietin levels rapidly increased after RIPC (p<0.01). Immunohistochemical staining revealed substantial expression of hypoxia inducible factor immediately after RIPC in mouse kidney. This suggested that RIPC activated the hypoxia inducible factor-erythropoietin pathway. To investigate the effect of RIPC-induced erythropoietin production on mouse heart, we examined the phosphorylation of signaling molecules downstream of the erythropoietin receptor, including STAT5 and AKT. We found that STAT5 was transiently phosphorylated and AKT was gradually phosphorylated in the hearts after RIPC. Finally, Evans blue and TTC staining in a mouse acute myocardial infarction model revealed that RIPC significantly reduced the infarct size (p<0.01) and concomitantly augmented the phosphorylation of STAT5 and AKT.
Conclusion: These results suggested that activation of the hypoxia inducible factor-erythropoietin pathway by RIPC may be a mechanism that contributes to cardioprotection during ischemia-induced myocardial injury.
- © 2011 by American Heart Association, Inc.