Abstract
Erythropoietin has recently been shown to have effects beyond hematopoiesis such as prevention of neuronal and cardiac apoptosis secondary to ischemia. In this study, we evaluated the in vivo protective potential of erythropoietin in the reperfused rabbit heart following ventricular ischemia. We show that "preconditioning" with erythropoietin activates cell survival pathways in myocardial tissue in vivo and adult rabbit cardiac fibroblasts in vitro. These pathways, activated by erythropoietin in both whole hearts and cardiac fibroblasts, are also activated acutely by ischemia/reperfusion injury. Moreover, in vivo studies indicate that erythropoietin treatment either prior to or during ischemia significantly enhances cardiac function and recovery, including left ventricular contractility, following myocardial ischemia/reperfusion. Our data indicate that a contributing in vivo cellular mechanism of this protection is mitigation of myocardial cell apoptosis. This results in decreased infarct size as evidenced by area at risk studies following in vivo ischemia/reperfusion injury, translating into more viable myocardium and less ventricular dysfunction. Therefore, erythropoietin treatment may offer novel protection against ischemic heart disease and may act, at least in part, by direct action on cardiac fibroblasts and myocytes to alter survival and ventricular remodeling.
Highlights
Erythropoietin has recently been shown to have effects beyond hematopoiesis such as prevention of neuronal and cardiac apoptosis secondary to ischemia
This results in decreased infarct size as evidenced by area at risk studies following in vivo ischemia/reperfusion injury, translating into more viable myocardium and less ventricular dysfunction
Since both cardiomyocytes and cardiac fibroblasts may contribute to post-ischemic ventricular remodeling, we extended our investigation to include an in vitro analysis of EPO-EPO-R signaling in these cells as a potential mediator of the EPO cardioprotection in vivo
Summary
Our data indicate that a contributing in vivo cellular mechanism of this protection is mitigation of myocardial cell apoptosis This results in decreased infarct size as evidenced by area at risk studies following in vivo ischemia/reperfusion injury, translating into more viable myocardium and less ventricular dysfunction. We investigated different doses and times of EPO administration relative to I/R injury to elucidate the most optimal protection scenario afforded by this cytokine Since both cardiomyocytes and cardiac fibroblasts may contribute to post-ischemic ventricular remodeling, we extended our investigation to include an in vitro analysis of EPO-EPO-R signaling in these cells as a potential mediator of the EPO cardioprotection in vivo. EPO directly activates similar pathways in adult cardiac fibroblasts suggesting that these cells may mediate, at least in part, cardioprotective effects of EPO
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