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.
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.
|Zhang, Ji; Qiao, Congzhen; Chang, Lin et al. (2016) Cardiomyocyte Overexpression of FABP4 Aggravates Pressure Overload-Induced Heart Hypertrophy. PLoS One 11:e0157372|
|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|
|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 277:162-70|
|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|
|Zhang, Weizhen; Chang, Lin; Zhang, Chao et al. (2015) Central and peripheral irisin differentially regulate blood pressure. Cardiovasc Drugs Ther 29:121-7|
|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|
|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|
|Zhang, Weizhen; Chang, Lin; Zhang, Chao et al. (2015) Irisin: A myokine with locomotor activity. Neurosci Lett 595:7-11|
|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 Î³ coactivator 1Î² (PGC-1Î²) protein attenuates vascular lesion formation by inhibition of chromatin loading of minichromosome maintenance complex in smooth muscle cells. J Biol Chem 288:4625-36|
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