Joseph Loscalzo, M.D., Ph.D.
Department of Medicine
New Research Building, Room 630
77 Avenue Louis Pasteur
Boston, MA 02115
Lab Members: 4 postdoctoral fellows, 3 graduate students
We are interested in the redox determinants of normal and abnormal blood vessel function and phenotype. Our specific focus has been on nitric oxide as an endothelial product that is susceptible to oxidative inactivation, the thiol proteome and its oxidative posttranslational modification, and the molecular responses of the endothelial cell to hypoxia.
Nitric oxide is a free radical that reacts readily with a variety of molecules in the vascular milieu to effect 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. Recently, we have also demonstrated the importance of key microRNAs induced by hypoxia that govern changes in the endothelial metabolome and metabolic phenotype, chief among which is miR210. This microRNA appears to regulate the conversion from oxidative phosphorylation to anaerobic glycolysis (the Pasteur effect), and to limit the cytotoxic production of mitochondrial oxidants.
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.
Chan, S.Y., Zhang, Y.-Y., Hemann, C., Mahoney, C.E., Zweier, J.L., and Loscalzo, J. (2009): MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab. 10:273-284.
Handy, D.E., Lubos, E., Yang, Y., Galbraith, J.D., Kelly, N., Zhang, Y.-Y., Leopold, J.A., and Loscalzo, J. (2009): Glutathione peroxidase-1 regulates mitochondrial function to modulate redox-dependent cellular responses. J.Biol.Chem. 284:11913-11921.
Kajstura, J., Rota, M., Hall, S.R., Hosoda, T., D’Amario, D., Sanada, F., Zheng, H., Ogorek, B., Rondon-Clavo, C., Ferreira-Martins, J., Matsuda, A., Arranto, C., Goichberg, P., Giordano, G., Haley, K.J., Bardelli, S., Rayatzadeh, H., Liu, X., Quaini, F., Liao, R., Leri, A., Perrella, M.A., Loscalzo, J., and Anversa, P. (2011): Human lung stem cells. N. Engl. J. Med. 364:1795-1806.
Barabasi, A.-L., Gulbahce, N., and Loscalzo, J. (2011); Network medicine: a network-.based approach to human disease. Nature Revs. Genet. 12:56-68.
For a complete listing of publications click here.
Last Update: 7/26/2012