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Dr. H. Linda Cai, MD, PhD Chief Investigator Cai Laboratory Email: hcai@mednet.ucla.edu Phone: (310) 267-2303 Fax: (310) 825-0132 UCLA David Geffen School of Medicine Department of Anesthesiology Division of Molecular Medicine 10833 Le Conte Ave BOX 951778, BH - 550 CHS Los Angeles, CA 90095-1778 |
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Current Projects:
Mechanisms for eNOS uncoupling by angiotensin II: Angiotensin II is a vaso-constrictive hormone and its production is often increased in cardiovascular diseases including hypertension, atherosclerosis and diabetic vascular diseases. We have recently shown that angiotensin II stimulates peroxynitrite formation via simultaneous production of superoxide and nitric oxide. This response is mediated by hydrogen peroxide, derived from an endothelial NAD(P)H oxidase. Peroxynitrite is capable of oxidizing eNOS cofactor tetrahydrobiopterin. Besides stimulation of peroxynitrite, we anticipate that angiotensin II also modulates the synthetic and salvage pathways of tetrahydrobiopterin. More recently, we found that prolonged angiotensin II stimulated superoxide production from eNOS in cultured endothelial cells. We are now actively investigating molecular mechanisms whereby this phenomenon occurs (manuscripts published in PNAS and Cir Res).
Angiotensin II and diabetic vascular diseases: Diabetes is one of the major risk factors for atherosclerotic vascular diseases. A majority of type 2 diabetic patients die of cardiovascular complications. We have had preliminary data suggesting angiotensin II interacts with high glucose to modulate eNOS function, ultimately contributing to diabetic vasculopathy. One of the projects in the laboratory is to investigate this observation further (manuscripts published in Diabetes & in preparation for Diabetologia).
Recoupling of eNOS in DOCA-salt-induced hypertension: Recently, DOCA-salt induced hypertension, a low rennin model of hypertension, was found associated with uncoupling of eNOS. We aim to identify novel therapeutics capable of recoupling eNOS to restore nitric oxide production. We have had promising preliminary data (manuscripts in revision to American Journal of Physiology).
Reactive oxygen species regulation of actin cytoskeleton: Actin cytoskeleton is an intracellular organelle that is critically important for signal transduction and gene regulation. In endothelial cells, reorganization of actin cytoskeleton is involved in cell proliferation and regulation of eNOS gene expression. We have identified a novel signaling pathway mediating hydrogen peroxide regulation of actin cytoskeleton (manuscript published in FEBS letter). Further experiments are designed to extend our observations to a deeper level.
Angiogenesis: role of reactive oxygen species: Angiogenesis is a process of new blood vessel formation. It is necessary for growth of solid cancer. In the vasculature, it is important for repair process. Therapeutic angiogenesis has been actively investigated as potential tools treating ischemic coronary artery disease. We are interested in how reactive oxygen species and nitric oxide interact to modulate angiogenesis (A novel pathway characterized was recently published in PNAS).
Cancer drugs and endothelial function: Some highly effective cancer drugs have limited usage due to their sometimes severe cardiovascular complications. We wonder whether modulation of endothelial function is one of the mechanisms and thus have an interesting project ongoing along this direction (manuscript in preparation).
