UPMC HEART AND VASCULAR INSTITUTE | UNIVERSITY OF PITTSBURGH | FIND PEOPLE
VMI
 


Vascular Medicine Institute
University of Pittsburgh
BST E1240
200 Lothrop Street
Pittsburgh, PA 15261
Phone: 412-383-5853
Fax: 412-648-5980

Patrick J. Pagano, PhD, FAHA

 

Patrick Pagano

 

Patrick Pagano, PhD, FAHA

Professor and Vice-Chair,
Graduate Education, Department of Pharmacology and Chemical Biology

Program Director, Molecular Pharmacology Graduate Program

E1247 BST
200 Lothrop Street
Pittsburgh, PA 15261

Office Phone: 412-383-6505
Lab Phone: 412-648-2610
Email: pagano@pitt.edu

Pagano Lab

   

Bio

Dr. Patrick Pagano received his Ph.D. from New York Medical College in 1991 and completed his postdoctoral training in 1994 at the Vascular Biology Unit at Boston University Medical Center Vascular Biology Unit in endothelial cell biology and vascular dysfunction.  Dr. Pagano began his independent career studying reactive oxygen species in the vasculature as an Assistant Professor of Medicine at Boston University Medical Center in 1996.  In 1998, Dr. Pagano joined the Hypertension and Vascular Research Division in the Department of Medicine at the Henry Ford Hospital in Detroit as Senior Staff Investigator. In 2003, he became the Division’s director of Vascular Biology Research.  He simultaneously held academic positions at Case Western University and Wayne State University.  In the summer of 2008, Dr. Pagano joined the Vascular Medicine Institute (VMI) as a tenured Professor in the Department of Pharmacology & Chemical Biology at the University of Pittsburgh, School of Medicine.

Research Interests

Dr. Pagano’s laboratory was among the first to identify a non-phagocytic NADPH oxidase (Nox) in the vascular wall, demonstrating a critical role for the essential subunit p67phox in its activity (Pagano et al 1995; Pagano et al, 1997).  His laboratory subsequently cloned vascular p67phox and illustrated its increased expression and activation in response to the potent pro-hypertensive hormone angiotensin II (Pagano et al, 1998), and developed the first specific Nox inhibitor (Rey et al, 2001).

       
   
  DHE staining in human pulmonary artery endothelial cells.   Representative color Doppler image of rat hindlimb blood flow. Red coloration of laser Doppler image indicates maximum and blue coloration indicates minimum blood flow.
       

The Pagano laboratory is also broadly recognized for pioneering work examining the role of adventitia-derived reactive oxygen species (ROS), in particular, superoxide anion (O2-) and hydrogen peroxide (H2O2), in the modulation of vascular tone, remodeling and inflammation.  Currently the laboratory is focused on novel Nox agonists and elucidating mechanistic insights into effector pathways upstream and downstream of Nox as they contribute to pulmonary hypertension, right heart failure, atherosclerosis and hyperproliferative disorders.

In recent years, Dr. Pagano and his group have made significant strides in the development of Nox therapeutics.  These include the development of a novel and potent inhibitor of Nox1 (Ranayhossaini et al, 2013) that is being aerosolized to in vivo models for the treatment of right ventricular failure in pulmonary hypertension.  Moreover, the Pagano laboratory has developed small molecule leads that are highly-selective for Nox2 (Cifuentes et al, 2013), which is implicated in myriad diseases from cardiopulmonary disease to neurodegenerative disorders and cancer. The pleotropic role of Noxs lends itself to wide utility of Nox drug development in diverse forms of human disease. 

NoxA1ds disrupts Nox1:NOXA1 interaction. FRET between Nox1-YFP and NoxA1-CFP transfected COS22 cells in the presence or absence of 10µM NoxA1ds or SCRMB.

NoxA1ds Mechanism of Action Schematic. The data presented here indicate that NoxA1ds binds to Nox1 and disrupts/prevents its VEGF-stimulated interaction with NOXA1, inhibiting endothelial cell migration [Ranayhossaini  DJ,  et al. J. Biol. Chem. (accepted), 2013].

Administration of Cy5-NoxA1ds by aerosolization shows lung localization in mouse. A nebulizer was used to administer Cy5-labeled NoxA1ds into mouse the images were captured by fluorescence molecular tomography (FMT). Bar graph shows quantification of Cy5 fluorescence in chest cavity at indicated times. The data support the utility of NoxA1ds as a therapeutic in pulmonary vascular disease.  

Key Publications

See Dr. Pagano's publications on PubMed.

Pagano PJ, Ito Y, Tornheim K, Gallop PM, Tauber AI, Cohen RA. An NADPH oxidase superoxide-generating system in the rabbit aorta. Am. J. Physiol. 268:H2274-H2280, 1995.

Pagano PJ, Clark JK, Cifuentes-Pagano ME, Clark SM, Callis GM, and Quinn MT. 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.

Pagano PJ, Chanock SL, Siwik DA, Colucci WS, and Clark JK. Angiotensin II induces p67phox mRNA expression and NADPH oxidase superoxide generation in rabbit aortic adventitial fibroblasts. Hypertension 32: 331-337, 1998.

Rey FE, Cifuentes ME, Kiarash A, Quinn MT, and Pagano PJ. 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.

Rey FE, Li XC, Carretero OA, Garvin JL, and Pagano PJ. Perivascular superoxide anion contributes to impairment of endothelium-dependent relaxation. Role of gp91phox. Circulation 106:2497-2502, 2002.

Liu J, Ormsby A, Oja-Tebbe N, and Pagano PJ. Gene transfer of NAD(P)H oxidase inhibitor to the vascular adventitia attenuates medial smooth muscle hypertrophy. Circ. Res. 95: 587-594, 2004.

Dourron HM, Jacobson GM, Park JL, Liu J, Reddy DJ, Scheel ML, and Pagano PJ. 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.

Haurani MJ, Cifuentes ME, Shepard AD, and Pagano PJ. Nox4 oxidase overexpression specifically decreases endogenous Nox4 mRNA and inhibits angiotensin II-induced adventitial myofibroblast migration. Hypertension. 52:143-9, 2008.

Ardanaz N, Yang XP, Cifuentes ME, Haurani MJ, Kyle JW, Liao TD, Carretero OA, and Pagano PJ. Lack of glutathione peroxidase-1 accelerates cardiac-specific hypertrophy and dysfunction in angiotensin II hypertension. Hypertension. 55:116-123, 2010.

Cascino T, Csanyi G, Al Ghouleh I, Montezano AC, Touyz RM, Haurani MJ, Pagano PJ. Adventitia-Derived Hydrogen Peroxide Impairs Relaxation of the Rat Carotid Artery via smooth muscle cell p38 Mitogen-Activated Protein Kinase. Antioxid Redox Signal. 2011; 15(6):1507-15, 2011.

Al Ghouleh I, Pagano PJEndosomal ClC-3 and Nox1: moving marksmen of redox signaling? Arterioscler Thromb Vasc Biol. 31(2):240-2, 2011.

Csányi G, Cifuentes-Pagano E, Al Ghouleh I, Ranayhossaini DJ, Egaña L, Lopes LR, Jackson HM, Kelley EE, Pagano PJ.  Nox2 B-loop peptide, Nox2ds, specifically inhibits the NADPH oxidase Nox2. Free Radic Biol Med. 51:1116-25, 2011.

Al Ghouleh, I, Khoo, N.K., Knaus, U.G., Griendling, K.K., Touyz, R.M., Thannickal,V.J., Barchowsky, A., Nauseef, W.M., Kelley, E.E., Bauer, P.M., Darley-Usmar, V., Shiva, S., Cifuentes-Pagano, E., Freeman, B.A., Gladwin, M.T., and Pagano, P.J.  Oxidases and peroxidases in cardiovascular and lung disease: new concepts in reactive oxygen species signaling. Free Rad Biol Med. 51:1271-1288, 2011.

Frazziano, G., Champion, H.C., and Pagano, P.JNADPH oxidase-derived ROS and the regulation of pulmonary vascular tone.  Am. J. Physiol., Heart & Circ., 302:H2166-2177, 2012.

Cifuentes-Pagano, M.E., Csányi, G., and Pagano, P.J.  NADPH oxidase inhibitors: A decade of discovery from Nox2ds to HTS.  Cell Mol. Life Sci., 69:2315-2325, 2012.

Ranayhossaini D, Pagano PJ. TrACEing angiotensin II type 1 to right ventricular hypertrophy: are the "sartans" a viable course to treating pulmonary arterial hypertension? Am J Respir Crit Care Med. 186(8):705-7, 2012.

Csányi G, Yao M, Rodriguez AI, Al Ghouleh I, Sharifi-Sanjani M, Frazziano G, Huang X, Kelley EE, Isenberg JS, Pagano PJ. Thrombospondin-1 regulates blood flow via CD47 receptor-mediated activation of NADPH oxidase 1Arterioscler Thromb Vasc Biol. 32:2966-2973, 2012.

Al Ghouleh I, Frazziano G, Rodriguez AI, Csanyi G, Maniar S, St Croix CM, Kelley EE, Egaña LA, Song GJ, Bisello A, Lee YJ, Pagano PJ. Aquaporin 1, Nox1 and Ask1 mediate oxidant-induced smooth muscle cell hypertrophy. Cardiovasc. Res. 97:134-142, 2013.

Cifuentes-Pagano E, Saha J, Csanyi G, Al Ghouleh I, Sahoo S, Rodriguez A, Wipf P, Pagano PJ, Skoda EM. Bridged tetrahydroisoquinolines as selective NADPH oxidase 2 (Nox2) inhibitors. Med Chem Comm.  4:1085-90, 2013.

Csányi, G., and Pagano, P.J.  Strategies aimed at Nox4 oxidase inhibition employing peptides from Nox4 B-loop and c-terminus and p22phox N-terminus: an elusive target.  Int. J. Hypertens.  2013:842827-, 2013.

Cifuentes-Pagano E, Meijles DN, Pagano PJ. Sly as a Nox: The challenges, triumphs and pitfalls of selective NADPH Oxidase inhibition. Antioxid Redox Signal. (2013) Sep 26. [Epub ahead of print]

Ghouleh IA, Rodríguez A, Pagano PJ, Csányi G. Proteomic Analysis Identifies an NADPH Oxidase 1 (Nox1)-Mediated Role for Actin-Related Protein 2/3 Complex Subunit 2 (ARPC2) in Promoting Smooth Muscle Cell Migration. Int J Mol Sci. 14(10):20220-35, 2013.

Ranayhossaini  DJ, Rodriguez AI, Sahoo S, Chen BB,  Mallampalli RK, Kelley EE, Csanyi G, Gladwin MT, Romero G, Pagano PJ. Selective Recapitulation of Conserved and Non-Conserved Regions of Putative NOXA1 Activation Domain Confers Isoform-Specific Inhibition of Nox1 Oxidase, Attenuation of Endothelial Cell Nox and Migration. J. Biol. Chem.  288:36437-36450 (2013).

Frazziano G, Al Ghouleh I, Baust J, Shiva S, Champion HC, Pagano PJ. Nox-derived ROS are acutely activated in pressure overload pulmonary hypertension: indications for a seminal role for mitochondrial Nox4. Am J Physiol Heart Circ Physiol. 2014; 306(2):H197-205. PubMed PMID: 24213612, PMCID: PMC3920131

Rogers NM, Sharifi-Sanjani M, Csányi G, Pagano PJ, Isenberg JS. Thrombospondin-1 and CD47 regulation of cardiac, pulmonary and vascular responses in health and disease. Matrix Biol. 2014; 37:92-101. PubMed PMID: 24418252, PMCID: PMC4096433

Cifuentes-Pagano E, Saha J, Csányi G, Ghouleh IA, Sahoo S, Rodríguez A, Wipf P, Pagano PJ, Skoda EM. Bridged tetrahydroisoquinolines as selective NADPH oxidase 2 (Nox2) inhibitors. Med Chem Comm. 2013; 4(7):1085-1092.PubMed PMID: 24466406, PMCID: PMC3897123

Yao M, Rogers NM, Csányi G, Rodriguez AI, Ross MA, St Croix C, Knupp H, Novelli EM, Thomson AW, Pagano PJ, Isenberg JS. Thrombospondin-1 activation of signal-regulatory protein-α stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury. J Am Soc Nephrol. 2014; 25(6):1171-86. Erratum in: J Am Soc Nephrol. 2014; 25(8):1884. PubMed PMID: 24511121, PMCID: PMC4033366

Hahn NE, Musters RJ, Fritz JM, Pagano PJ, Vonk AB, Paulus WJ, van Rossum AC, Meischl C, Niessen HW, Krijnen PA. Early NADPH oxidase-2 activation is crucial in phenylephrine-induced hypertrophy of H9c2 cells. Cell Signal. 2014; 26(9):1818-24. PubMed PMID: 24794531

Rodríguez AI, Csányi G, Ranayhossaini DJ, Feck DM, Blose KJ, Assatourian L, Vorp DA, Pagano PJ. MEF2B-Nox1 signaling is critical for stretch-induced phenotypic modulation of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2015; 35(2):430-8. PubMed PMID: 25550204