: In this proposal, we will investigate the role of adventitia-derived superoxide O2 in vascular reactivity, hypertrophy and injury response in hypertension. The proposal stems from our previous findings (a) documenting expression of phagocyte-like NADPH oxidase components in the adventitia of arteries: (b) demonstrating that this enzyme is the major source of vascular O2 (C) demonstrating that p67Ph0x. a critical component in phagocyte NADPH oxidase activity is essential to vascular oxidase activity: (d) showing that AngII-induced elevation of vascular O2 is associated with transcriptional activation of adventitial NADPH oxidase: and (e) demonstrating that now el inhibitors of this enzyme attenuate AngII-induced O2 production. While our data have established the presence of a vascular NADPH oxidase source of O2 and revealed some of its molecular character. little is known of its regulation, or the significance of its location in the adventitia. We will address tine physiological significance of NADPH oxidase by testing tine hypothesis that increased vascular levels of O2 via adventitial NADPH oxidase expression and assembly of its components during the development of AngII-dependent hypertension impair endothelium-dependent responses. and enhance the medial in hypertrophic response and neointimal proliferative response to injury, in testing this hypothesis. we will (1) examine a variety of cell-permeant chimeric peptide sequences that we developed as to their effectiveness in blocking assembly of the oxidase, vascular O2 generation, and attenuating AngII-dependent blood pressure elevation: (2) target these NADPH oxidase inhibitors to various vascular cell types by adenoviral transfection and development of a transgenic mouse model and examine tine effect on endothelium-dependent responses: (3) examine the effect of cell targeting on medial hypertrophy. and compare responses in glutathione peroxidase-l-deficient versus wild-type mice (4) examine the effect of cell targeting on mvofibroblast migration and neointimal proliferation during the vascular injury response.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055425-08
Application #
6832251
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Barouch, Winifred
Project Start
1996-04-01
Project End
2006-11-30
Budget Start
2004-12-01
Budget End
2006-11-30
Support Year
8
Fiscal Year
2005
Total Cost
$214,500
Indirect Cost
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
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Cascino, Thomas; Csanyi, Gabor; Al Ghouleh, Imad et al. (2011) Adventitia-derived hydrogen peroxide impairs relaxation of the rat carotid artery via smooth muscle cell p38 mitogen-activated protein kinase. Antioxid Redox Signal 15:1507-15
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Ardanaz, Noelia; Yang, Xiao-Ping; Cifuentes, M Eugenia et al. (2010) Lack of glutathione peroxidase 1 accelerates cardiac-specific hypertrophy and dysfunction in angiotensin II hypertension. Hypertension 55:116-23
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Cifuentes, M E; Rey, F E; Carretero, O A et al. (2000) Upregulation of p67(phox) and gp91(phox) in aortas from angiotensin II-infused mice. Am J Physiol Heart Circ Physiol 279:H2234-40