Welcome to the homepage of the Cai Laboratory! We belong to the Division of Molecular Medicine, Department of Anesthesiology. We are also part of the Cardiovascular Research Laboratories and Department of Medicine, Division of Cardiology. As the Principle Investigator of the group, I appreciate you visiting our webpage and hope that you find our research exciting.
We are interested in reactive oxygen species regulation of endothelial nitric oxide synthase (eNOS) function, and its consequences regarding nitric oxide bioavailability and development of cardiovascular, repiratory and metabolic diseases. Nitric oxide is an important signaling molecule. It relaxes vascular smooth muscle to dilate blood vessels. It also inhibits a variety of pathological events such as activation of platelets and induction of inflammatory proteins. Loss of nitric oxide leads to high blood pressure and atherosclerotic vascular diseases. It is of great clinical significance to fully understand regulation of nitric oxide bioavailability at molecular levels.
Data accumulated in the past decade have shown that production of reactive oxygen species is increased in aging, cardiovascular and pulmonary diseases, neurodegenerative disorders and angiogenesis. An important consequence of excessive production of reactive oxygen species, e.g. following initial activation of membrane bound NADPH oxidase (NOX), is oxidative inactivation of nitric oxide (e.g. invited review by our group, Nature Reviews Cardiology 2020). For example, superoxide radicals rapidly react with nitric oxide to form peroxynitrite, resulting in immediate loss of nitric oxide. Additional studies suggest that reactive oxygen species can oxidize tetrahydrobiopterin, an essential cofactor for eNOS. This response leads to a condition where eNOS produces superoxide rather than nitric oxide. This "uncoupling" phenomenon of eNOS likely prolongs oxidative stress. Our goal is to characterize in-depth molecular mechanisms whereby eNOS uncouples under disease states. This will ultimately lead to discovery of novel therapeutics restoring nitric oxide production from uncoupled eNOS, in other words, "recoupling" of eNOS. Over the years we have identified an innovative and critial role of tetrahydrobiopterin salvage enzyme dihydrofolate reductase (DHFR) deficiency in mediating cardiovascular pathogenesis (e.g. PNAS 2005, Diabetes 2007, Hypertension 2012, Diabetes 2014, Hypertension 2019, Redox Biology 2019, 2020, 2021), and robust therapeutic efficacies of restroing DHFR function.
One focus in the lab is to explore molecular mechanisms and consequences of eNOS uncoupling in various forms of vascular diseases such as hypertension, abdominal aortic aneurysm, atherosclerosis, and diabetic vascular disease using a combination of molecular and cell biological, genetic and physiological approaches. We are also interested in defining nitric oxide-dependent innovative angiogenic pathways (PNAS 2006, Circ Res 2009), oxidative mechanisms of ischemia reperfusion (I/R) induced cardiac injury and protection by a novel protein netrin-1 (J Mol Cell Cardiol 2010-2014, PNAS 2015), molecular mechanisms underlying the most common cardiac arrhythmia atrial fibrillation and its thromboembolic complications (Circulation 2012, J Biol Chem 2014), and a causal role of vascular oxidative stress of development of obesity and metabolic syndrome (Diabetes 2014). We have also been studying novel molecular mechanisms and therapeutics of COVID-19 since the outbreak of the pandemic (Lancet Respiratory Medicine 2000, Pharmacology and Therapeutics 2021, Redox Biology 2021). Please refer to the Publications page for the full list of our publications/research directions and lastest advancements in a diverse range of projects.
