Recent studies suggest that development of coronary artery disease (CAD) is associated with an enhanced expression of bone morphogenic proteins (BMPs) and TNFct. TNFct and BMP2/4 are pro-inflammatory cytokines that induce endothelial activation and promote monocyte adhesion. Despite the pathophysiological importance of BMP2/4 and TNFa, the mechanisms that regulate the expression of these cytokines in coronary arteries are completely unknown. I found that in aortic banded rats coronary arteries and forelimb arteries which are exposed to high pressure exhibit an increased oxidative stress and an up-regulation of pro-inflammatory cytokines, whereas arteries (located downstream from the coarctation) of the same animals which are exposed to normal pressure exhibit normal O2"""""""" production and phenotype. In cultured endothelial cells oxidative stress and oscillatory shear stress was shown to enhance the transcription of BMPs. On the basis of these observations and extensive preliminary results I propose that coronary arterial BMP and TNFa expression is regulated by athero-prone hemodynamic forces. The overall goal of the proposed project is to test the hypothesis that athero-prone hemodynamic forces increase ROS generation and activate redox-sensitive transcription factors in endothelial and/or smooth muscle cells of coronary arteries with the consequent up-regulation of BMPs and TNFa, which induce endothelial activation, up-regulating cellular adhesion molecules and enhancing monocyte adhesion to the endothelium. To investigate the effects of different pressure and shear stress conditions and dissect the underlying molecular mechanisms both an in vivo model (aortic constriction-induced coronary arterial hypertension) and a novel vessel culture system will be used.
Aim #1 : To determine whether athero-prone hemodynamic forces regulate expression of BMPs and TNFa in coronary arteries.
Aim #2 : To elucidate the link between athero-prone hemodynamic forces, increased levels of O2"""""""", H2O2 and/or ONOO"""""""" and expression of pro-inflammatory cytokines in endothelial and smooth muscle cells.
Aim #3 : To determine whether athero-prone hemodynamic forces activate NF-KB, AP-1 and/or PARS in coronary arteries and whether these transcription factors regulate expression of BMPs and TNFa.
Aim #4 : To elucidate the mechanisms by which BMPs elicit endothelial activation promoting monocyte adhesion in coronary arteries. The identification of these novel cellular and molecular mechanisms involved in early pro-atherogenic alterations in coronary arteries may ultimately lead to specific therapeutic interventions preventing the development of CAD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077256-03
Application #
7367970
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Srinivas, Pothur R
Project Start
2006-03-15
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
3
Fiscal Year
2008
Total Cost
$346,648
Indirect Cost
Name
New York Medical College
Department
Physiology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Ungvari, Zoltan; Ridgway, Iain; Philipp, Eva E R et al. (2011) Extreme longevity is associated with increased resistance to oxidative stress in Arctica islandica, the longest-living non-colonial animal. J Gerontol A Biol Sci Med Sci 66:741-50
Ungvari, Zoltan; Csiszar, Anna (2011) Resveratrol confers endothelial protection in insulin-dependent diabetes mellitus: editorial to: ""Resveratrol shows vasoprotective effect reducing oxidative stress without affecting metabolic disturbances in insulin-dependent diabetes of rabbits"" by F. Cardiovasc Drugs Ther 25:111-3
Ungvari, Zoltan; Sonntag, William E; de Cabo, Rafael et al. (2011) Mitochondrial protection by resveratrol. Exerc Sport Sci Rev 39:128-32
Csiszar, Anna (2011) Anti-inflammatory effects of resveratrol: possible role in prevention of age-related cardiovascular disease. Ann N Y Acad Sci 1215:117-22
Ungvari, Zoltan; Philipp, Eva E R (2011) Comparative gerontology--from mussels to man. J Gerontol A Biol Sci Med Sci 66:295-7
Ungvari, Zoltan; Bailey-Downs, Lora; Gautam, Tripti et al. (2011) Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. Am J Physiol Heart Circ Physiol 300:H1133-40
Ungvari, Zoltan; Bailey-Downs, Lora; Sosnowska, Danuta et al. (2011) Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. Am J Physiol Heart Circ Physiol 301:H363-72
Ungvari, Zoltan; Bailey-Downs, Lora; Gautam, Tripti et al. (2011) Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-{kappa}B activation in the nonhuman primate Macaca mulatta. J Gerontol A Biol Sci Med Sci 66:866-75
Ungvari, Zoltan; Sosnowska, Danuta; Podlutsky, Andrej et al. (2011) Free radical production, antioxidant capacity, and oxidative stress response signatures in fibroblasts from Lewis dwarf rats: effects of life span-extending peripubertal GH treatment. J Gerontol A Biol Sci Med Sci 66:501-10
Ungvari, Zoltan; Sonntag, William E; Csiszar, Anna (2010) Mitochondria and aging in the vascular system. J Mol Med (Berl) 88:1021-7

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