The Michel lab uses biochemical and cell biological approaches to explore signal transduction pathways in the cells and tissues of the cardiovascular system, with a particular focus on the metabolism of nitric oxide (NO) and hydrogen peroxide (H2O2) in endothelial cells and cardiac myocytes. We study these pathways in cultured cells, in informative mouse models, and in human disease states.
Nitric oxide has been studied for many years as the active compound formed from drugs such as nitroglycerin. The endothelial isoform of nitric oxide synthase (eNOS) is a key signaling enzyme that is activated by a variety of cell surface receptors and is involved in the control of vascular smooth muscle relaxation, cardiac myocyte function, and platelet aggregation.
Some of our recent studies have exploited novel biosensors in cellular imaging studies to explore the relationship between nitric oxide and reactive oxygen species. For example, we have been using the H2O2 biosensor HyPer2 to study receptor-modulated H2O2 metabolism using live cell imaging approaches both in cardiac myocytes and in endothelial cells.
We have also been exploring the roles of “statin” drugs (HMG CoA reductase inhibitors commonly used in the treatment of cardiovascular disease) in eNOS and H2O2 signaling. We are seeking to understand the roles of statins in the differential modulation of eNOS and in the metabolism of reactive oxygen species. We found that statins activate the small GTPase Rac1, a cytoskeleton-associated regulatory protein with key roles both in eNOS regulation and in the generation of reactive oxygen species implicated in vascular physiology and pathophysiology. We discovered that Rac1 and H2O2 regulate the MARCKS protein, an enigmatic actin-binding protein that plays a key role in regulation of endothelial permeability.
We are also studying the role of NO and H2O2 in regulating the AMP-activated protein kinase (AMPK) and other kinases involved in eNOS signaling in endothelial cells and in the heart, with a particular interest in the perturbations of these pathways in diabetes and in response to oxidative stress.