Cardiovascular disease (CVD) is the number one killer and a major cause of disability in the United States. Emerging data suggest that overproduction of reactive oxygen species (ROS) plays a causal role in the pathogenesis of atherosclerosis and other CVD. Reactive nitrogen intermediates such as peroxynitrite (ONOO-) and nitrogen-dioxide radicals, formed by rapid reaction between nitric oxide (.NO) and ROS, react with carbohydrates, DNA bases, protein tyrosine/tryptophan, and unsaturated fatty acids to form relatively stable nitrated products. In the past eight years, our research team has revealed that a novel class of nitrated unsaturated fatty acids (NO2-FA) is generated by NO- mediated oxidative reactions and exerts pleiotropic cell signaling actions with a property of anti-oxidative stress. Recently, we have well documented that NO2- FA exerted anti-proliferative and pro-apoptotic effects in vascular smooth muscle cells (VSMC) via activation of Nrf2 with an increase in Nrf2 stability in vitro. Furthermore, we have demonstrated that NO2-FA inhibited vascular lesion formation after arterial injury. These key results let us to test our central hypothesis that NO2-FA-operated Nrf2 signaling play a critical role in protecting vasculature from vascular lesion formation, thereby contributing to maintenance of vascular homeostasis. As Nrf2 signaling is critical for the anti-oxidative defense in various organs including the cardiovascular system, understanding of the endogenous NO2-FA-operated Nrf2 signaling will provide novel insights into redox homeostasis and the development of new therapeutic strategies for the treatment of CVD. Specifically, we will 1) Define NO2-FA-operated Nrf2 signaling in the control of VSMC fate in vitro;2) Define the mechanisms of NO2-FA- mediated Nrf2 activation in VSMC;3) Determine the NO2-FA-operated Nrf2 signaling as a "vasculo-protective" determinant in vascular lesion formation in vivo.

Public Health Relevance

Cardiovascular disease (CVD) is the number one killer and a major cause of disability in the United States. Overproduction of reactive oxygen species (ROS) plays a causal role in the pathogenesis of CVD;however, nonselective approach of scavenging all ROS appears to have deleterious effects. This proposal will address the "vasculo-protective" effect of nitro-fatty acids (NO2-FA), which is mediated by activation of Nrf2 signaling, an anti-oxidative system. The outcome of these studies will provide novel perspectives for the rational design and development of NO2-FA derivatives with unique properties of enhancing of anti-oxidative defense rather than simply blockade of ROS production for CVD treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105114-03
Application #
8287650
Study Section
Special Emphasis Panel (ZRG1-VH-D (03))
Program Officer
Gao, Yunling
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$525,933
Indirect Cost
$128,446
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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