Hypertension imparts a series of complex humoral and mechanical signals to the arterial wall that result in the development of an inflammatory state. Recent studies have implicated the production of reactive oxygen species as central to the pathogenesis of hypertensive vascular pathology. In this application, we propose to test the hypothesis that in the setting of hypertension, local production of hydrogen peroxide by vascular smooth muscle cells, endothelial cells and/or resident macrophages is a pivotal signaling event in the inflammatory responses that occur in the hypertensive arterial wall. To accomplish this overall objective we have developed a novel transgenic mouse that will allow tissue-specific overexpression of catalase. Through these studies we will be able to modify local H2O2 production at the cellular level and determine the subsequent effects on production of reactive oxygen species, inflammatory gene expression and the development of hypertension-induced atherosclerosis. The proposed specific aims are: I: To determine the effects of smooth muscle-specific overexpression of catalase on the development of hypertension-induced inflammation and atherosclerosis. II: Examine the comparative effects of macrophage-specific overexpression of catalase on the vascular consequences of hypertension. III: To determine the potential functional contributions endothelial-specific overexpression of catalase on vascular function, inflammation and the progression of hypertension-induced atherosclerosis.

Public Health Relevance

Hypertension is a major health problem in the United States today. The pathological consequences of hypertension are myriad and include atherosclerosis, stroke, heart failure, kidney failure and other end organ disease. The proposed studies in this application will investigate the potential role of localized H2O2 production in vascular inflammatory responses in an effort to define the causal role of H2O2 in the pathogenesis of hypertensive vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090584-04
Application #
8116635
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2008-09-04
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$348,750
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Lyle, Alicia N; Remus, Ebony W; Fan, Aaron E et al. (2014) Hydrogen peroxide regulates osteopontin expression through activation of transcriptional and translational pathways. J Biol Chem 289:275-85
Remus, Ebony Washington; Lyle, Alicia N; Weiss, Daiana et al. (2013) miR181a protects against angiotensin II-induced osteopontin expression in vascular smooth muscle cells. Atherosclerosis 228:168-74
Parastatidis, Ioannis; Weiss, Daiana; Joseph, Giji et al. (2013) Overexpression of catalase in vascular smooth muscle cells prevents the formation of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 33:2389-96
Zhang, Huanchun; Taylor, W Robert; Joseph, Giji et al. (2013) mRNA-binding protein ZFP36 is expressed in atherosclerotic lesions and reduces inflammation in aortic endothelial cells. Arterioscler Thromb Vasc Biol 33:1212-20
Remus, Ebony Washington; O'Donnell Jr, Robert E; Rafferty, Kathryn et al. (2012) The role of lysyl oxidase family members in the stabilization of abdominal aortic aneurysms. Am J Physiol Heart Circ Physiol 303:H1067-75
Hodara, Roberto; Weiss, Daiana; Joseph, Giji et al. (2011) Overexpression of catalase in myeloid cells causes impaired postischemic neovascularization. Arterioscler Thromb Vasc Biol 31:2203-9
Pendergrass, Karl D; Varghese, Susan T; Maiellaro-Rafferty, Kathryn et al. (2011) Temporal effects of catalase overexpression on healing after myocardial infarction. Circ Heart Fail 4:98-106
Willett, Nick J; Kundu, Kousik; Knight, Sarah F et al. (2011) Redox signaling in an in vivo murine model of low magnitude oscillatory wall shear stress. Antioxid Redox Signal 15:1369-78
Maiellaro-Rafferty, Kathryn; Weiss, Daiana; Joseph, Giji et al. (2011) Catalase overexpression in aortic smooth muscle prevents pathological mechanical changes underlying abdominal aortic aneurysm formation. Am J Physiol Heart Circ Physiol 301:H355-62
Kundu, Kousik; Knight, Sarah F; Lee, Seungjun et al. (2010) A significant improvement of the efficacy of radical oxidant probes by the kinetic isotope effect. Angew Chem Int Ed Engl 49:6134-8

Showing the most recent 10 out of 13 publications