NAD(P)H oxidases are broadly activated in cardiovascular diseases, including hypertension, atherosclerosis, and diabetes. Reactive oxygen species (ROS) derived from these oxidases have been implicated in impaired vascular relaxation, medial hypertrophy, and neointimal hyperplasia in various forms of hypertension. NAD(P)H oxidase-derived superoxide anion (O2-) and other ROS are believed to mediate stretch-induced signaling, leading to neointimal hyperplasia. We previously developed a cell-permeant inhibitor of gp91-phox- (nox2-) based oxidase assembly which is capable of abrogating vascular O2- production in response to angiotensin II. The current proposal stems from 3 major findings, demonstrating (a) the importance of the multi-component oxidase assembly in vascular O2- production;(b) the ability of our cell-permeant inhibitor of nox2-based oxidase assembly to inhibit O2- and attenuate neointimal proliferation of the rat carotid artery in response to balloon angioplasty;and (c) the upregulation of novel nox2 homologues, nox1 and nox4, in response to balloon injury. Since nox1 and nox4 appear to be important oxidase homologues involved differentially in vascular O2- production after stretch, we will determine the efficacy of docking sequence mimics (which inhibit nox1and nox4 assembly with other oxidase subunits) to inhibit whole-vessel and endothelial, smooth muscle cell and fibroblast O2- generation and neointimal proliferation. These studies will address the hypothesis that nox1 and nox4 are functionally involved in vascular stretch-induced oxidase assembly and O2- generation, leading to neointimal proliferation.
Three specific aims will be tested: (1) to develop specific inhibitors of nox1- and nox4-based oxidases and test them in an in vitro model of hormone-induced vascular NAD(P)H oxidase activation;(2) to investigate the role of docking sequences on individual nox-based oxidases in vascular stretch-induced oxidase activity in vitro;and (3) to determine the role of nox docking sequences in balloon angioplasty-induced neointimal hyperplasia in vivo. Relevance: Therapies aimed at disrupting the various NAD(P)H oxidase systems in blood vessels should substantially improve vascular patency and function following balloon angioplasty. These inhibitors are also expected to provide broad utility in a variety of disease processes involving oxidants, including hypertension, diabetes and atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079207-04
Application #
7595170
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Goldman, Stephen
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
4
Fiscal Year
2009
Total Cost
$373,226
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Meijles, Daniel N; Sahoo, Sanghamitra; Al Ghouleh, Imad et al. (2017) The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1. Sci Signal 10:
Csányi, Gábor; Feck, Douglas M; Ghoshal, Pushpankur et al. (2017) CD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL. Antioxid Redox Signal 26:886-901
Li, Yao; Pagano, Patrick J (2017) Microvascular NADPH oxidase in health and disease. Free Radic Biol Med 109:33-47
Ghouleh, Imad Al; Sahoo, Sanghamitra; Meijles, Daniel N et al. (2017) Endothelial Nox1 oxidase assembly in human pulmonary arterial hypertension; driver of Gremlin1-mediated proliferation. Clin Sci (Lond) 131:2019-2035
Al Ghouleh, Imad; Meijles, Daniel N; Mutchler, Stephanie et al. (2016) Binding of EBP50 to Nox organizing subunit p47phox is pivotal to cellular reactive species generation and altered vascular phenotype. Proc Natl Acad Sci U S A 113:E5308-17
Sahoo, Sanghamitra; Meijles, Daniel N; Al Ghouleh, Imad et al. (2016) MEF2C-MYOCD and Leiomodin1 Suppression by miRNA-214 Promotes Smooth Muscle Cell Phenotype Switching in Pulmonary Arterial Hypertension. PLoS One 11:e0153780
Meijles, Daniel N; Pagano, Patrick J (2016) Nox and Inflammation in the Vascular Adventitia. Hypertension 67:14-9
Sahoo, Sanghamitra; Meijles, Daniel N; Pagano, Patrick J (2016) NADPH oxidases: key modulators in aging and age-related cardiovascular diseases? Clin Sci (Lond) 130:317-35
Quesada, I M; Lucero, A; Amaya, C et al. (2015) Selective inactivation of NADPH oxidase 2 causes regression of vascularization and the size and stability of atherosclerotic plaques. Atherosclerosis 242:469-75
Mukawera, Espérance; Chartier, Stefany; Williams, Virginie et al. (2015) Redox-modulating agents target NOX2-dependent IKK? oncogenic kinase expression and proliferation in human breast cancer cell lines. Redox Biol 6:9-18

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