It is becoming increasingly evident that nitric oxide (NO)-derived reactive species (RNS) mediate diverse vascular cell signaling and pathogenic processes. RNS oxidize and nitrate carbohydrates, DNA, protein, and unsaturated fatty acids. Although significant understanding exists regarding the -NO-dependent nitration of protein (e.g. tyrosine residues to 3-nitrotyrosine), little is known related to nitrated lipids. Nitrated fatty acids (nitroalkenes) are clinically abundant molecules present in the human circulation at micromolar levels and are now appreciated as a novel class of signaling molecules. The physiological relevance and mechanisms of signal transduction induced by nitroalkenes need to be better defined. Of significance, we have recently identified nitrolinoleic acid (LNO2) as a potent peroxisome proliferator-activated receptor (PPAR) gamma ligand, suggesting that the PPARgamma-signaling pathway will be a key mediator of LNO2-regulated effects. Preliminary studies document that LNO2 exerts pro-apoptotic and growth-inhibitory effects in VSMC. In addition, exogenous administration of LNO2 inhibits vascular lesion formation in balloon-injured rat carotid arteries. Furthermore, computer modeling of LNO2/PPARgamma interaction reveals that R288 and C285 in the PPARgamma ligand binding domain may interact directly with the NO2 moiety of LNO2. These results support the working hypothesis that activation of PPARgamma by LN02 inhibits vascular lesion formation by decreasing VSMC proliferation and promoting apoptosis. This hypothesis will be tested by systematically implementing structure-function analysis of LNO2/PPARgamma pathway with both a loss- and gain-of-function strategy using both in vitro and in vivo model systems. Specifically, we will: 1). Determine the molecular mechanisms mediating LNO2 activation of PPARgamma;2). Define the role of the LNO2-mediated PPARgamma signaling in the regulation of VSMC proliferation and survival;3). Define whether LNO2-dependent PPARgamma activation serves to inhibit vascular lesion formation. This proposed research plan will provide important insights into the signaling actions of the LNO2/PPARgamma pathway as a critical inhibitor of vascular inflammation and lesion formation. Advances in understanding the mechanisms of endogenous PPARgamma modulation will provide novel therapeutic strategies for treating obesity/diabetes and cardiovascular disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Hasan, Ahmed AK
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
Savastano, Luis E; Zhou, Quan; Smith, Arlene et al. (2017) Multimodal laser-based angioscopy for structural, chemical and biological imaging of atherosclerosis. Nat Biomed Eng 1:
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
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
Li, Shen; Wang, Yan-Ning; Niimi, Manabu et al. (2016) Angiotensin II Destabilizes Coronary Plaques in Watanabe Heritable Hyperlipidemic Rabbits. Arterioscler Thromb Vasc Biol 36:810-816
Guo, Yanhong; Garcia-Barrio, Minerva T; Wang, Laiyuan et al. (2016) Experimental Biology for the Identification of Causal Pathways in Atherosclerosis. Cardiovasc Drugs Ther 30:1-11
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, Haoming; Lauver, D Adam; Wang, Hui et al. (2016) Significant Improvement of Antithrombotic Responses to Clopidogrel by Use of a Novel Conjugate as Revealed in an Arterial Model of Thrombosis. J Pharmacol Exp Ther 359:11-7
Schwendeman, Anna; Sviridov, Denis O; Yuan, Wenmin et al. (2015) The effect of phospholipid composition of reconstituted HDL on its cholesterol efflux and anti-inflammatory properties. J Lipid Res 56:1727-37
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

Showing the most recent 10 out of 82 publications