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)
National Heart, Lung, and Blood Institute (NHLBI)
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, Yanbo; Lu, Haocheng; Liang, Wenying et al. (2018) Endothelial TFEB (Transcription Factor EB) Positively Regulates Postischemic Angiogenesis. Circ Res 122:945-957
Zhang, Ji; Qiao, Congzhen; Chang, Lin et al. (2016) Cardiomyocyte Overexpression of FABP4 Aggravates Pressure Overload-Induced Heart Hypertrophy. PLoS One 11:e0157372
Zhang, J; Yuan, L; Zhang, X et al. (2016) Altered long non-coding RNA transcriptomic profiles in brain microvascular endothelium after cerebral ischemia. Exp Neurol 277:162-170
Villacorta, Luis; Gao, Zhen; Schopfer, Francisco J et al. (2016) Nitro-fatty acids in cardiovascular regulation and diseases: characteristics and molecular mechanisms. Front Biosci (Landmark Ed) 21:873-89
Fan, Yanbo; Lu, Haocheng; Guo, Yanhong et al. (2016) Hepatic Transmembrane 6 Superfamily Member 2 Regulates Cholesterol Metabolism in Mice. Gastroenterology 150:1208-1218
Zhang, Weizhen; Chang, Lin; Zhang, Chao et al. (2015) Central and peripheral irisin differentially regulate blood pressure. Cardiovasc Drugs Ther 29:121-7
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
Guo, Yanhong; Fan, Yanbo; Zhang, Jifeng et al. (2015) Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production. J Clin Invest 125:3819-30
Meng, Zhuo-Xian; Wang, Lin; Chang, Lin et al. (2015) A Diet-Sensitive BAF60a-Mediated Pathway Links Hepatic Bile Acid Metabolism to Cholesterol Absorption and Atherosclerosis. Cell Rep 13:1658-69
Zhang, Weizhen; Chang, Lin; Zhang, Chao et al. (2015) Irisin: A myokine with locomotor activity. Neurosci Lett 595:7-11

Showing the most recent 10 out of 29 publications