Cardiovascular disease is the leading cause of morbidity and mortality in the US, and sex differences are well established. Cardiovascular disease is often characterized by inappropriate cardiomyocyte death. Adult cardiomyocytes are post-mitotic cells which undergo very limited cell division. Thus, cardiomyocyte death as occurs during myocardial infarction has very detrimental consequences. In spite of considerable effort, the mechanisms responsible for cardiomyocyte death are poorly understood. This lack of mechanistic understanding is a major contributor to the failure to translate cardioprotective drugs to the clinic. The overall goal of the research effort of my laboratory is to use a multipronged, interactive approach to elucidate the mechanisms responsible for cardiomyocyte death and to define cardioprotective strategies. Projects 1 and 2 are focused on developing a better understanding of the mechanisms responsible for cardiomyocyte death. It is widely hypothesized that an increase in cytosolic calcium initiates cell death by entering mitochondria on the mitochondrial calcium uniporter (MCU) to activate a large conductance channel in the inner mitochondrial membrane known as the permeability transition pore (PTP) and that opening of this pore leads to necroptosis, a regulated form of necrotic cell death. Strategies to reduce PTP opening either by inhibiting the PTP directly or inhibiting the rise in its activator, mitochondrial calcium, have been proposed. A major limitation of developing strategies to inhibit the PTP is the lack of knowledge about the identity of the protein(s) that form the PTP and details of how PTP is activated by calcium and cyclophilin D (CypD), a matrix protein which activates PTP. Project 1, (orange in Figure 1) examines the mechanism by which CypD activates the PTP. We defined several novel post-translational modifications (PTM) of CypD and demonstrate that these PTMs integrate multiple signaling pathways and thereby regulate the activity of the PTP. We also characterized new inhibitors of PTP that work independently of CypD. We further examined the role of nitric oxide (NO) signaling and S-nitros(yl)ation (SNO), an NO dependent PTM, in regulating the PTP and other pathways of cardioprotection. Ongoing studies will test the hypothesis that complex V is a component of the PTP, and we will continue to elucidate the role of CypD in regulating the PTP. We will also examine cross-talk in cysteine PTMs. Project 2 (blue) focuses on the regulation of mitochondrial calcium, a key activator of the PTP and cell death. We published several studies examining the role of MCU and its regulatory proteins, MICU1 and EMRE in controlling mitochondrial calcium and ischemia-reperfusion (I/R) injury Future studies will continue to dissect the role of MCU and its regulatory proteins in regulating matrix calcium and PTP opening. We will also use a newly developed method to measure matrix calcium in a beating perfused heart. This will allow us to directly test the role of MCU and its regulators in regulating matrix calcium and the role of matrix calcium in activating the PTP. Project 3 (purple) focuses on sex differences in cardioprotection. We demonstrated that estrogen can mediate cardioprotection by activating extra-nuclear estrogen receptors. We defined sex differences in a PPAR network in hypertrophy ADDIN EN.CITE we will follow this up in future studies. Future studies will also test for sex differences in mitochondrial calcium uptake during I/R.
Meet the Team
Elizabeth Murphy, Ph.D.
Dr. Elizabeth Murphy received her PhD from the University of Pennsylvania in Biochemistry, followed by postdoctoral studies in Physiology and then an assistant research professor at Duke University Medical Center. Before joining the NHLBI in 2006 as the head of the Cardiac Physiology Section, she was the head of the Cell Biology Group at the National Institute of Environmental Health Sciences. She became a Fellow of the American Heart Association in 2001 and a Fellow of the International Society for Heart Research in 2007; she received the NHLBI Award for Outstanding Mentorship in 2011. Dr. Murphy has authored or co-authored more than 200 papers and reviews. Dr. Murphy is a member of the American Heart Association-Council of Basic Cardiovascular Research, American Physiological Society, and International Society for Heart Research. She served as president of the International Society for Heart Research from 2016 to 2019. She serves as Deputy Editor of Circulation Research. She is also the North American Coordinator of a Leducq Transatlantic Network of Excellence on Targeting Mitochondria to Treat Heart Disease. She received the Peter Harris Research Achievement Award from the International Society for Heart Research in 2020.