Nitro-Fatty Acids and Nrf2 in Vascular Remodeling

Summary

Principal Investigator: Yuqing Eugene Chen
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2010-07-01 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. pmc Nitro-oleic acid inhibits angiotensin II-induced hypertension
    Jifeng Zhang
    Cardiovascular Center, College of Engineering, University of Michigan, USA
    Circ Res 107:540-8. 2010
  2. pmc Electrophilic nitro-fatty acids inhibit vascular inflammation by disrupting LPS-dependent TLR4 signalling in lipid rafts
    Luis Villacorta
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, North Campus Research Complex Building 26 Room 355S, 2800 Plymouth Road, Ann Arbor, MI, USA
    Cardiovasc Res 98:116-24. 2013
  3. pmc Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) protein attenuates vascular lesion formation by inhibition of chromatin loading of minichromosome maintenance complex in smooth muscle cells
    Yanhong Guo
    Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Biol Chem 288:4625-36. 2013
  4. pmc Human apolipoprotein A-II protects against diet-induced atherosclerosis in transgenic rabbits
    Yao Wang
    Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo City, Yamanashi, Japan
    Arterioscler Thromb Vasc Biol 33:224-31. 2013
  5. pmc Novel keto-phospholipids are generated by monocytes and macrophages, detected in cystic fibrosis, and activate peroxisome proliferator-activated receptor-γ
    Victoria J Hammond
    School of Medicine, Cardiff University, Heath Park Campus, Cardiff CF14 4XN, United Kingdom
    J Biol Chem 287:41651-66. 2012
  6. pmc Krüppel-like factor-11, a transcription factor involved in diabetes mellitus, suppresses endothelial cell activation via the nuclear factor-κB signaling pathway
    Yanbo Fan
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Arterioscler Thromb Vasc Biol 32:2981-8. 2012
  7. pmc Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-γ deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis
    Lin Chang
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Circulation 126:1067-78. 2012
  8. pmc Yap1 protein regulates vascular smooth muscle cell phenotypic switch by interaction with myocardin
    Changqing Xie
    Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Biol Chem 287:14598-605. 2012
  9. pmc Endothelial lipase mediates HDL levels in normal and hyperlipidemic rabbits
    Jifeng Zhang
    Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo City, Japan
    J Atheroscler Thromb 19:213-26. 2012
  10. ncbi MicroRNA and vascular smooth muscle cells
    Changqing Xie
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA
    Vitam Horm 87:321-39. 2011

Research Grants

  1. Metabolic Stress-Induced Fatty Acid Nitration and Cardiovascular Function
    Marsha P Cole; Fiscal Year: 2013
  2. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
  3. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
  4. Redox Regulation of SERCA by Nitric Oxide
    Richard A Cohen; Fiscal Year: 2013
  5. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
  6. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
  7. Oxidant stress and diabetic endothelial dysfunction
    Ming Hui Zou; Fiscal Year: 2013
  8. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
  9. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
  10. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013

Detail Information

Publications14

  1. pmc Nitro-oleic acid inhibits angiotensin II-induced hypertension
    Jifeng Zhang
    Cardiovascular Center, College of Engineering, University of Michigan, USA
    Circ Res 107:540-8. 2010
    ..OA-NO(2) exerts cell signaling actions as a result of its strong electrophilic nature and mediates pleiotropic cell responses in the vasculature...
  2. pmc Electrophilic nitro-fatty acids inhibit vascular inflammation by disrupting LPS-dependent TLR4 signalling in lipid rafts
    Luis Villacorta
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, North Campus Research Complex Building 26 Room 355S, 2800 Plymouth Road, Ann Arbor, MI, USA
    Cardiovasc Res 98:116-24. 2013
    ....
  3. pmc Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) protein attenuates vascular lesion formation by inhibition of chromatin loading of minichromosome maintenance complex in smooth muscle cells
    Yanhong Guo
    Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Biol Chem 288:4625-36. 2013
    ....
  4. pmc Human apolipoprotein A-II protects against diet-induced atherosclerosis in transgenic rabbits
    Yao Wang
    Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo City, Yamanashi, Japan
    Arterioscler Thromb Vasc Biol 33:224-31. 2013
    ..We aimed to examine whether apo A-II plays any role in atherogenesis and, if so, to elucidate the mechanism involved...
  5. pmc Novel keto-phospholipids are generated by monocytes and macrophages, detected in cystic fibrosis, and activate peroxisome proliferator-activated receptor-γ
    Victoria J Hammond
    School of Medicine, Cardiff University, Heath Park Campus, Cardiff CF14 4XN, United Kingdom
    J Biol Chem 287:41651-66. 2012
    ..The lipids are a new family of bioactive mediators from the 12/15-LOX pathway that may contribute to its known anti-inflammatory actions in vivo...
  6. pmc Krüppel-like factor-11, a transcription factor involved in diabetes mellitus, suppresses endothelial cell activation via the nuclear factor-κB signaling pathway
    Yanbo Fan
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Arterioscler Thromb Vasc Biol 32:2981-8. 2012
    ..However, the function of KLF11 in the cardiovascular system still remains to be uncovered. In this study, we aimed to investigate the role of KLF11 in vascular endothelial inflammation...
  7. pmc Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-γ deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis
    Lin Chang
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Circulation 126:1067-78. 2012
    ..We hypothesize that the thermogenic function of PVAT regulates intravascular temperature and reduces atherosclerosis...
  8. pmc Yap1 protein regulates vascular smooth muscle cell phenotypic switch by interaction with myocardin
    Changqing Xie
    Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Biol Chem 287:14598-605. 2012
    ....
  9. pmc Endothelial lipase mediates HDL levels in normal and hyperlipidemic rabbits
    Jifeng Zhang
    Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo City, Japan
    J Atheroscler Thromb 19:213-26. 2012
    ....
  10. ncbi MicroRNA and vascular smooth muscle cells
    Changqing Xie
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA
    Vitam Horm 87:321-39. 2011
    ..Here, we review recent advances regarding functions of specific miRNAs in vasculature and discuss possible mechanisms by which miRNAs affect VSMC biology...
  11. pmc Inhibition of gluconeogenic genes by calcium-regulated heat-stable protein 1 via repression of peroxisome proliferator-activated receptor α
    Yanbo Fan
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
    J Biol Chem 286:40584-94. 2011
    ..Our data suggest that CARHSP1 inhibits hepatic gluconeogenic gene expression via repression of PPARα and that CARHSP1 may be a molecular target for the treatment of diabetes...
  12. pmc Vascular PPARδ protects against stroke-induced brain injury
    Ke Jie Yin
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Arterioscler Thromb Vasc Biol 31:574-81. 2011
    ..To investigate the effects of peroxisome proliferator-activated receptor (PPAR)δ in the cerebral vasculature following stroke-induced brain injury...
  13. pmc Vascular smooth muscle cell peroxisome proliferator-activated receptor-γ mediates pioglitazone-reduced vascular lesion formation
    Milton Hamblin
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA
    Arterioscler Thromb Vasc Biol 31:352-9. 2011
    ..In this study, we investigated the role of VSMC PPARγ-mediated signaling in transplantation-associated vascular lesion formation...

Research Grants30

  1. Metabolic Stress-Induced Fatty Acid Nitration and Cardiovascular Function
    Marsha P Cole; Fiscal Year: 2013
    ..This work is of substantial clinical relevance as it will also provide insight as to the potential efficacy of OA-NO2 formed as an adaptive cell signaling mediator in hyperglycemic-induced myocardial injury. ..
  2. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  3. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  4. Redox Regulation of SERCA by Nitric Oxide
    Richard A Cohen; Fiscal Year: 2013
    ..Our proposed studies intend to demonstrate the role for this mechanism in vivo using mouse models of diabetic vascular disease, including a mouse that expresses a mutant SERCA that lacks the key thiol. ..
  5. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  6. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  7. Oxidant stress and diabetic endothelial dysfunction
    Ming Hui Zou; Fiscal Year: 2013
    ..abstract_text> ..
  8. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  9. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  10. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  11. Vascular Oxidases in Migration
    Kathy K Griendling; Fiscal Year: 2013
    ..Understanding the mechanisms underlying migration may lead to the development of new therapeutic strategies that can be carefully and specifically targeted to the critically important events in disease initiation. ..
  12. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..
  13. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
    ..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..
  14. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
    ..abstract_text> ..
  15. Role of Eosinophils in Airway Inflammation and Remodeling
    Nizar N Jarjour; Fiscal Year: 2013
    ..Given the prominence of eosinophilic inflammation in a significant proportion of severe asthma patients, these advances will have direct implications for the patients most affected by this very common illness. ..
  16. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..