Mary O. Gray, M.D. Assistant Professor of Medicine in Residence mail: San Francisco General Hospital 1001 Potrero Ave., 5G1 UCSF Box 0846 San Francisco, CA 94110 phone: (415) 206-8613 fax: (415) 206-5100 email: gray@medicine.ucsf.edu

Education

Stanford University, BS, 1983, Biology and English

University of California, San Diego, MD, 1987, Medicine

Professional Experience

Dr. Gray trained in Internal Medicine at UC San Diego and in Cardiovascular Medicine at UC San Francisco. She has been on the faculty in the Department of Medicine at San Francisco General Hospital since 2001 and was appointed director of Cardiology and Anticoagulation Clinics in 2002. She joined the Lung Biology Research Center as a principal investigator in April 2004.

Research Interests

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 δ-opioid receptor agonists can reduce infarction and improve myocardial recovery after prolonged ischemia-reperfusion. Selective activation of PKCε is a signaling event common to many cardioprotective strategies. Our laboratory demonstrated that inhibition of PKCε 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 PKCε knockout mice. Identification of effector molecules downstream of PKCε is an area of intense investigation. Investigators from independent laboratories observe that activated PKCε 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 PKCεactivation 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. PKC. 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.

Selected Publications

Jin ZQ, Zhou HZ, Zhu P, Mochly-Rosen D, Messing RO, Goetzl EJ, Karliner JS, Gray MO. Cardioprotection mediated by sphingosine-1-phosphate and ganglioside GM-1 in wild-type and εPKC knockout mice. Am J Physiol: Heart and Circ Physiol 2002; 282:H1970-H1977.

Zhou HZ, Karliner, Gray MO. Moderate alcohol consumption induces cardiac protection by activating protein kinase C εand Akt. Am J Physiol: Heart and Circ Physiol 2002; 283:H165-H174.

Maklashina E, Sher Y, Zhou HZ, Gray MO, Karliner JS, Cecchini G. Effect of anoxia / reperfusion on reversible active / de-active transition of NADH-ubiquinone oxidoreductase (Complex I) in rat heart. Biochim Biophys Acta 2002;1556:6-12.

Gray MO, Zhou HZ, Schafhalter-Zoppoth I, Zhu P, Mochly-Rosen D, Messing RO. Preservation of baseline hemodynamic function and loss of inducible cardiac protection in mice lacking protein kinase C ε J Biol Chem 2004; 279:3596-3604.

Zhou HZ, Swanson RA, Simonis U, Ma XK, Cecchini G, Gray MO. Mitochondrial respiratory chain Complex I function contributes to the cardioprotection caused by inhibition or disruption of poly(ADP-ribose) polymerase-1. J Biol Chem. In Revision.