Novel strategies are needed to protect against cardiac ischemia-reperfusion injury. Coronary heart disease is a leading cause of death worldwide. Existing therapies improve prognosis associated with acute coronary syndromes including unstable angina. However, patients with these disorders remain at high risk of myocardial infarction, heart failure, and death. Mechanisms of ischemia-reperfusion injury and strategies to reduce heart, brain, and renal damage should be further explored.

Cardioprotective signaling pathways may require protein kinase C (PKC) activation. Pretreatment of animal hearts with brief ischemia or pharmacological agents such as ethanol, adenosine receptor agonists, or d-opioid receptor agonists can reduce infarction and improve myocardial recovery after prolonged ischemia-reperfusion. Selective activation of PKCe is a signaling event common to many cardioprotective strategies. Our laboratory demonstrated that inhibition of PKCe translocation and binding to selective anchoring proteins blocked protection of cardiac myocytes from hypoxia-induced cell death. Recently, we established that cardioprotection induced by ischemic and pharmacological pretreatment is blocked in the hearts from PKCe knockout mice. Identification of effector molecules downstream of PKCe is an area of intense investigation. Investigators from independent laboratories observe that activated PKCe physically associates with myocyte proteins in multiple subcellular compartments including the cytoskeleton, Golgi complex, and mitochondria.

Metabolic pathways and mitochondria regulate responses to oxidative stress. The central hypothesis of our current research activity is that myocardial metabolism and mitochondrial function are important regulators of both tissue injury and viability in response to prolonged ischemia-reperfusion. For example, we test the importance of PKCe activation for preservation of myocardial NAD+, lactate, and ATP by using modulators of PKC isozyme translocation and function in perfused mouse hearts or in cultured adult mouse cardiac myocytes. We also measure the effects of oxidative stress on mitochondrial function in whole organelles and submitochondrial particles.

We have begun investigation of how other signaling pathways modulate beneficial effects of preconditioning. PKCe precipitates mitochondrial dysfunction and tissue necrosis by enhancing formation of toxic reactive oxygen species (ROS). Similarly, poly(ADP-ribose)polymerase-1 (PARP-1) can promote contractile dysfunction and infarction by depleting cardiac NAD+ and ATP stores. Complementary approaches using in vitro, ex vivo, and in vivo models may lead to new strategies for prevention of ischemic heart disease. Opportunities for research are available, particularly for fellows interested in metabolism and cardiovascular effects of ethanol consumption. Collaborations with investigators outside of cardiovascular medicine are welcome.