Research Interests:

Nitric oxide biological chemistry, oxidative stress, post-translational protein modifications.  Non-invasive discovery and validation of disease biomarkers.

Keywords:

Nitric oxide, oxidative stress, 3-nitrotyrosine, S-nitrosothiols.

Research Summary:

A major effort in my laboratory has been directed towards the identification and quantification of proteins modified post-translationally by reactive species in human diseases.  Oxidative stress and most critically stress induced by reactive nitrogen species has been implicated as a common molecular pathway for the development of pathological phenotypes in a variety of human disorders.  We discovered that selective nitration and oxidation of tyrosine residues is one of the major consequences of oxidative stress and formation of reactive nitrogen species. Proteins nitrated on tyrosine residues have been detected in all major organs in more than 60 human disorders. Recent efforts include the use of proteomics to identify proteins that are nitrated in human diseases such as respiratory distress syndromes and coronary artery disease.  Ongoing efforts are focused on the nitration of fibrinogen in coronary artery disease patients. Other studies utilizing structure-function biochemical and biophysical approaches investigate the sites of tyrosine nitration and more critically the consequences of this modification on protein function.  Moreover, the utility of tracking the changes in nitrated and oxidized plasma proteins as non-invasive predictors of disease development, disease outcome or as surrogate markers for determining the efficacy of therapeutic interventions is being evaluated in human populations. Finally, we are exploring the possibility of utilizing protein tyrosine nitration and oxidation to heighten immune responses and to augment the function of proteins in the coagulation cascade.

Potential Lab Rotation Projects:

Proteomic analysis of proteins modified by nitration in human plasma and atherosclerotic lesions.

Dynamic regulation of tyrosine nitration in human platelets.

Investigate the interaction of nitrated fibrinogen and fibrin with endothelial cells and monocytes.

Development of unbiased complementary approaches for the proteomic evaluation of S-nitrosocysteine modified proteins in endothelial and vascular smooth muscle cells.

Key References:

Paxinou, E., Weisse, M., Chen, Q., Souza, J.M., Hertkorn, C., Selak, M., Daikhin, E., Yudkoff, M., Sowa, G., Sessa, W.C. and Ischiropoulos, H., Dynamic regulation of metabolism and respiration by endogenously produced nitric oxide protects against oxidative stress. Proc. Natl. Acad. Sci. USA 98: 11575-11580, 2001.

Gow AJ, Chen Q, Hess DT, Day,,B, Ischiropoulos, H* and. Stamler JS* Basal and stimulated protein S-nitrosylation in multiple cell types and tissues. J. Biol. Chem. 277:9637-9640, 2002.

Fries, D.M., Paxinou, E., Themistocleous, M., Swanberg, E., Griendling, K.K., Salvemini, D., Slot, J.W., Heijnen, H.F.G. Hazen, S.L. and Ischiropoulos, H. Expression of inducible nitric oxide synthase and intracellular protein tyrosine nitration in vascular smooth muscle cells: role of reactive oxygen species. J. Biol. Chem. 278:22901-22907, 2003.

Vadseth, C., Souza, J.M., Thomson, L., Seagraves, A., Nagaswami, C., Scheiner, T., Torbet, J., Vilaire, G., Bennett, J.S., Murciano, J-C., Muzykantov, V., Penn, M.S., Hazen, S.L., Weisel, J.W. and Ischiropoulos, H. Pro-thrombotic state induced by post translational modification of fibrinogen by reactive nitrogen species. J. Biol. Chem. 279:8820-6, 2004.