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Pagano Lab
Eugenia Cifuentes Pagano, PhD
Dr. Cifuentes-Pagano's research interests focus on the understanding of the molecular mechanisms of action of novel NADPH oxidase isoforms and their regulation in the vasculature. The phagocyte NADPH oxidase (or respiratory burst oxidase) is a well-characterized reactive oxygen species (ROS)-generating system that catalyzes the one-electron reduction of oxygen to O2-, the precursor to a variety of other reactive oxygen species. The NADPH oxidase paradigm is a multi-subunit enzyme complex that includes two membrane-spanning subunits, p22-phox and nox2 , and three cytoplasmic subunits, p40-phox, p47-phox and p67-phox. Our laboratory was the first to discover a nox2-based oxidase in the vasculature and to develop specific inhibitors targeting this robust source of ROS. Since that initial discovery, various isoforms of NADPH oxidase have been described which differ from the nox2 system in unique modifications of their nox-subunit amino acid sequence as well as the cytoplasmic components that they require. Besides their structural differences, the various isoforms present differential tissue and cellular distribution. The multi-level complexity of this family of proteins provides an opportunity to develop new tools to dissect the role of each of the isoforms in vascular function and pathology.
http://paganolab.pitt.edu/
Link: Translational Program Project / Vascular Sub-Phenotypes of Lung Disease http://www.vmi.pitt.edu/tPPG.html
Dr. Pagano's research focuses on the modulatory role of the adventitia in vascular function and structure under both physiological and pathophysiological conditions. Dr. Pagano's laboratory was among the first to identify a non-phagocytic NADPH oxidase in the vascular wall, demonstrating a critical role for essential subunit p67phox in its activity. He subsequently cloned vascular p67phox and illustrated its potent activation at the mRNA and protein level in response to the potent pro-hypertensive hormone angiotensin II. Stemming from these early discoveries, Dr. Pagano was the first to develop specific cell- and tissue-permeant peptidic and adenoviral inhibitor of NADPH oxidase, which is widely considered the most specific NADPH oxidase inhibitor available. These and his other more recently developed inhibitors of novel isoforms of NADPH oxidase are expected to provide a platform for the development of new therapies aimed at treating hypertension and other cardiovascular diseases. Moreover, Dr. Pagano is broadly recognized for his pioneering work examining the role of adventitia-derived reactive oxygen species (ROS) and, in particular, superoxide anion and hydrogen peroxide in the modulation of vascular tone, inflammation, and remodeling.
http://www.vmi.pitt.edu/pagano.html
Research Assistant Professor
Research Info
Development of peptic, viral and small molecular inhibitors of NADPH oxidases and reactive species to assess NOX involvement in cardiovascular disease as well as to devise new therapies
Csanyi G, E Cifuentes-Pagano, I Al Ghouleh, DJ Ranayhossaini, L Egana, LR Lopes, HM Jackson, EE Kelley and PJ Pagano. Nox2 B-loop peptide, Nox2ds, specifically inhibits the NADPH oxidase Nox2. Free Radic Biol Med 51:1116-1125, 2011.
Ardanaz N, XP Yang, ME Cifuentes, MJ Haurani, KW Jackson, TD Liao, OA Carretero and PJ Pagano. Lack of glutathione peroxidase 1 accelerates cardiac-specific hypertrophy and dysfunction in angiotensin II hypertension. Hypertension 55:116-123, 2010.
Haurani MJ, ME Cifuentes, AD Shepard and PJ Pagano. Nox4 oxidase overexpression specifically decreases endogenous Nox4 mRNA and inhibits angiotensin II-induced adventitial myofibroblast migration. Hypertension 52(1):143-149, 2008.
Cifuentes ME and PJ Pagano. Targeting reactive oxygen species in hypertension. Curr Opin Nephrol Hypertens 15:179-186, 2006.
Cifuentes ME and PJ Pagano. c-Src and smooth muscle NAD(P)H oxidase: Assembling a path to hypertrophy. Arterioscler Thromb Vasc Biol 23:919-921, 2003.
Rey FE, ME Cifuentes, A Kiarash, MT Quinn and PJ Pagano. Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O2- and systolic blood pressure in mice. Circ Res 89:408-414, 2001.
Cifuentes ME, F Rey, OA Carretero and PJ Pagano. Upregulation of p67(phox) and gp91(phox) in aortas from angiotensin II-infused mice. Am J Physiol Heart Circ Physiol 279:H2234-H2240, 2000.
Pagano PJ, JK Clark, ME Cifuentes-Pagano, SM Clark, GM Callis and MT Quinn. Localization of a constitutively active, phagocyte-like NADPH oxidase in rabbit aortic adventitia: enhancement by angiotensin II. Proc Natl Acad Sci USA 94:4483-14488, 1997.
Ardanaz N, XP Yang, ME Cifuentes, MJ Haurani, KW Jackson, T Liao and PJ Pagano. Lack of glutathione peroxidase 1 accelerates cardiac-specific hypertrophy and dysfunction in angiotensin II hypertension. Hypertension 55:116-123, 2010.
Haurani MJ, ME Cifuentes, AD Shepard and PJ Pagano. Nox4 oxidase overexpression specifically decreases endogenous Nox4 mRNA and inhibits angiotensin II-induced adventitial myofibroblast migration. Hypertension 52:143-149, 2008.
Dourron, H.M., G.M. Jacobson, J.L. Park, J. Liu, D.J. Reddy, M.L. Scheel, and P.J. Pagano. Perivascular gene transfer of an NADPH oxidase inhibitor suppresses angioplasty-induced neointimal proliferation of rat carotid artery. Am. J. Physiol. Heart Circ. Physiol. 288: H946-H953, 2005.
Liu, J., A. Ormsby, N. Oja-Tebbe, and P.J. Pagano. Gene transfer of NAD(P)H oxidase inhibitor to the vascular adventitia attenuates medial smooth muscle hypertrophy. Circ. Res. 95: 587-594, 2004.
Rey, F.E., X.-C. Li, O.A. Carretero, J.L. Garvin, and P.J. Pagano. Perivascular superoxide anion contributes to impairment of endothelium-dependent relaxation. Role of gp91phox . Circulation 106:2497-2502, 2002.
Rey, F.E., M.E. Cifuentes, A. Kiarash, M.T. Quinn, and P.J. Pagano. A novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O2 and systolic blood pressure in mice. Circ. Res. 89: 408-414, 2001.
Pagano PJ, SL Chanock, DA Siwik, WS Colucci and JK Clark. Angiotensin II induces p67phox mRNA expression and NADPH oxidase superoxide generation in rabbit aortic adventitial fibroblasts. Hypertension 32:331-337, 1998.
Pagano, P.J., J.K. Clark, M.E. Cifuentes-Pagano, S.M. Clark, G.M. Callis, and M.T. Quinn. Localization of a constitutively active, phagocyte-like NADPH oxidase in rabbit aortic adventitia: enhancement by angiotensin II. Proc. Natl. Acad. Sci. USA 94: 14483-14488, 1997.