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.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gao, Yunling
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
Zip Code
Fan, Jianglin; Kitajima, Shuji; Watanabe, Teruo et al. (2015) Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine. Pharmacol Ther 146:104-19
Brown, Nicholas K; Zhou, Zhou; Zhang, Jifeng et al. (2014) Perivascular adipose tissue in vascular function and disease: a review of current research and animal models. Arterioscler Thromb Vasc Biol 34:1621-30
Guo, Yanhong; Fan, Yanbo; Zhang, Jifeng et al. (2013) Peroxisome proliferator-activated receptor ýý coactivator 1ýý (PGC-1ýý) protein attenuates vascular lesion formation by inhibition of chromatin loading of minichromosome maintenance complex in smooth muscle cells. J Biol Chem 288:4625-36
Villacorta, Luis; Chang, Lin; Salvatore, Sonia R et al. (2013) Electrophilic nitro-fatty acids inhibit vascular inflammation by disrupting LPS-dependent TLR4 signalling in lipid rafts. Cardiovasc Res 98:116-24
Wang, Yao; Niimi, Manabu; Nishijima, Kazutoshi et al. (2013) Human apolipoprotein A-II protects against diet-induced atherosclerosis in transgenic rabbits. Arterioscler Thromb Vasc Biol 33:224-31
Zhang, Jifeng; Yu, Ying; Nakamura, Kae et al. (2012) Endothelial lipase mediates HDL levels in normal and hyperlipidemic rabbits. J Atheroscler Thromb 19:213-26
Xie, Changqing; Guo, Yanhong; Zhu, Tianqing et al. (2012) Yap1 protein regulates vascular smooth muscle cell phenotypic switch by interaction with myocardin. J Biol Chem 287:14598-605
Hamblin, Milton; Chang, Lin; Zhang, Hengmin et al. (2011) Vascular smooth muscle cell peroxisome proliferator-activated receptor-? mediates pioglitazone-reduced vascular lesion formation. Arterioscler Thromb Vasc Biol 31:352-9
Xie, Changqing; Zhang, Jifeng; Chen, Y Eugene (2011) MicroRNA and vascular smooth muscle cells. Vitam Horm 87:321-39
Yin, Ke-Jie; Deng, Zhen; Hamblin, Milton et al. (2011) Vascular PPARýý protects against stroke-induced brain injury. Arterioscler Thromb Vasc Biol 31:574-81

Showing the most recent 10 out of 12 publications