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18th World Congress on Heart Disease



Linda Cai, M.D., Ph.D., UCLA David Geffen School of Medicine, CA, USA


It has become clear during the past decade that endothelial nitric oxide synthase (eNOS) can transform into a superoxide-generating/pro-oxidant enzyme, when its essential cofactor tetrahydrobiopterin (H4B) becomes deficient. This phenomenon is now referred to as eNOS uncoupling. During the past 7-8 years my laboratory has pioneered the discovery that endothelial dihydrofolate reductase (DHFR) is critical for physiological regulation of nitric oxide (NO) production; and that a DHFR deficiency mediates angiotensin II uncoupling of eNOS in cultured endothelial cells, (Proc Natl Acad Sci U S A. 2005), hypertensive mice (Journal of Molecular and Cellular Cardiology 2009), and animals with type 1 diabetes mellitus (Diabetes 2007). Our group has further shown that folic acid administration is highly effective in recoupling eNOS via restoration of DHFR function (Journal of Molecular and Cellular Cardiology 2009; Hypertension 2011). Our latest work has identified upstream signaling events leading to dysfunction of DHFR in pathological conditions that involve activation of NADPH oxidases. Follow-up studies from other independent groups confirming our observations on the key regulatory role of DHFR in cardiovascular pathophysiology will also be discussed.




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