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About Loscalzo Lab

Taken from http://www.hms.harvard.edu/dms/bbs/fac/loscalzo.html

We are interested in the vascular biology of endothelial cells and platelets and their role in atherosclerosis and thrombosis.  In particular, the laboratory has focused much of its efforts in recent years on the biology and pathobiology of nitric oxide in the vasculature using molecular, genetic, biochemical, cellular, and animal approaches.  A product of normal endothelial cells, nitric oxide is a deceptively simple heterodiatomic molecule derived from the oxidation of L-arginine that controls vascular smooth muscle tone, inhibits platelet activation, impairs leukocyte adhesion, and inhibits smooth muscle proliferation.  A deficiency of bioactive nitric oxide, caused either by endothelial dysfunction or by free radical inactivation, promotes thrombosis and atherogenesis.

Nitric oxide is a free radical that reacts readily with a variety of molecules in the vascular milieu to effects its biologic actions.  Chief among these are molecules bearing thiol functionalities which, in the presence of molecular oxygen, lead to the formation of S-nitrosothiols or thionitrites.  The unique biologic actions of these naturally occurring nitric oxide adducts have served as a major focus of the laboratory’s research efforts.  Both low-molecular-weight and protein thiols react with nitric oxide to form the corresponding S-nitrosothiols; modification of protein thiols in this manner represents a form of post-translational modification that alters protein function and cell phenotype. 

Cellular redox state also affects the reactivity of nitric oxide and its bioactivity, as well as regulates the transcription of the nitric oxide synthase gene(s).  Redox regulation of nitric oxide synthesis and reactivity, and its role in normal vascular biology and pathobiology, form a central research focus in the laboratory. 

Key antioxidant enzymes that attenuate the flux of reactive oxygen species in endothelial cells include the glutathione peroxidases (selenocysteine-containing oxidoreductases) and glucose-6-phosphate dehydrogenase, a key source of NADPH and, thus, of the glutathione-glutathione disulfide redox couple.  We have identified acquired and heritable abnormalities in these antioxidant enzymes, termed oxidative enzymopathies, that correlate with common cardiovascular diseases, including atherosclerosis, thrombosis, and hypertension.  The redox consequences of deficiencies of these antioxidant enzymes on the endothelial proteome has been a recent area of investigation.  Using the thiol proteome as a redox target, we have developed methods to isolate, characterize, and explore the functional consequences of changes in the redox state of susceptible thiol functionalities by systems-based approaches.   Redox state changes, including S-nitrosation and disulfide formation, appear to have both structural and functional consequences for the thiol proteome and its actions within the cell.  Oxidative posttranslational modification of the proteome is, thus, a central signaling mechanism in response to changes in cell redox state that modulates cell phenotype in health and disease. These studies are relevant to the molecular pathogenesis of atherosclerosis, systemic hypertension, pulmonary hypertension, and thrombotic vascular disorders.

 

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