Effectors of AMPK Signaling for Treatment of Myocardial Ischemia/Reperfusion Injury
Costa, Robert John, II
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Myocardial ischemia is a condition that occurs when blood flow to the myocardium is reduced due to coronary atherosclerosis, coronary thrombosis, and the narrowing of arterioles in the heart. Current treatments for myocardial infarction are largely targeted at immediate restoration of blood flow to the heart by recanalization of the occluded coronary artery via the use of percutaneous coronary intervention, thrombolytics, and anticoagulants. These interventions, however, have the risk of exacerbating injury and bleeding in patients who may already be at an increased risk due to other medications or conditions. Therefore, there is an urgent need for novel therapeutic strategies that can limit myocardial ischemia/reperfusion (I/R) injury without increasing the risk of bleeding. Recently our lab has found Activated Protein C (APC) to have cardioprotective effects via the AMPK signaling pathway. However, the specific downstream mechanisms elicited by AMPK due to APC induced activation are poorly understood. AMPK has been shown to protect against myocardial ischemic injury through the regulation of metabolism in the heart by balancing the energy demand and supply in response to ischemic stress. There is increasing evidence that enhancing glucose oxidation and inhibiting fatty acid oxidation in the ischemic heart has a beneficial effect for maintaining cardiac efficiency. For this reason, novel therapeutics that can selectively target the up regulation of glucose metabolism in the ischemic heart may be of high value. Therefore, current research is aimed at further characterizing the beneficial effects of using novel AMPK agonists for modulating cardiac substrate metabolism to prevent myocardial infarction.