Methylarginines and Vascular Injury

Summary

Principal Investigator: Arturo J Cardounel
Abstract: The long term objective of this proposal is to establish Protein Arginine Methyltransferases and Dimethyarginine Dimethylaminohydrolase (DDAH), the enzymes responsible for methylarginine synthesis and metabolism, as a key regulator of endothelial function. It is our hypothesis that the increased plasma ADMA observed in cardiovascular disease is a biomarker of DDAH activity and that many of the endothelial affects attributed to ADMA are directly manifested through altered DDAH-PRMT activity. We have shown that in addition to the direct effects of ADMA on eNOS activity, DDAH modulates endothelial NO production through ADMA independent mechanisms involving altered protein-methylation and amino acid metabolism. The goals of the current proposal are to: 1.) identify the pathways of ADMA metabolism in the endothelium;2.) determine the mechanisms through which DDAH modulates endothelial protein-arginine methylation and define the effects of protein methylation on endothelial function;3.) determine the mechanisms through which DDAH regulates endothelial L-arginine metabolism and the consequences on endothelial NO production;and 4.) identify the mechanisms through which the PRMT-DDAH-ADMA axis regulates endothelial function and atherosusceptibility. For each of these aims, a combination of cellular, molecular, biophysical and physiological approaches will be used to characterize the effects of DDAH on endothelial function using in vitro and in vivo models. Results from these studies will provide fundamental mechanistic information regarding the mechanisms through which the PRMT-DDAH-ADMA axis modulates cellular function and may lead to new approaches to treat vascular disease.
Funding Period: 2005-07-01 - 2014-11-30
more information: NIH RePORT

Top Publications

  1. ncbi Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular function
    Arturo J Cardounel
    Department of Pharmacology, Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA
    J Biol Chem 282:879-87. 2007
  2. pmc Age and exercise training alter signaling through reactive oxygen species in the endothelium of skeletal muscle arterioles
    Amy L Sindler
    Department of Physiology and Pharmacology, and the Center for Interdisciplinary Research in Cardiovascular Sciences, West Virginia University School of Medicine, Morgantown, West Virginia, USA
    J Appl Physiol (1985) 114:681-93. 2013
  3. pmc Suppression of eNOS-derived superoxide by caveolin-1: a biopterin-dependent mechanism
    Kanchana Karuppiah
    Department of Anesthesiology, Ohio State University, Columbus, Ohio, USA
    Am J Physiol Heart Circ Physiol 301:H903-11. 2011
  4. pmc Superoxide induces endothelial nitric-oxide synthase protein thiyl radical formation, a novel mechanism regulating eNOS function and coupling
    Chun An Chen
    Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA
    J Biol Chem 286:29098-107. 2011
  5. pmc S-glutathionylation reshapes our understanding of endothelial nitric oxide synthase uncoupling and nitric oxide/reactive oxygen species-mediated signaling
    Jay L Zweier
    1 Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio
    Antioxid Redox Signal 14:1769-75. 2011
  6. pmc Role of dimethylarginine dimethylaminohydrolases in the regulation of endothelial nitric oxide production
    ARTHUR J POPE
    Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida 32607, USA
    J Biol Chem 284:35338-47. 2009
  7. pmc Role of the PRMT-DDAH-ADMA axis in the regulation of endothelial nitric oxide production
    ARTHUR J POPE
    Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, 32607, United States
    Pharmacol Res 60:461-5. 2009
  8. ncbi Regulation of eNOS-derived superoxide by endogenous methylarginines
    Lawrence J Druhan
    Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA
    Biochemistry 47:7256-63. 2008
  9. ncbi Mechanism of 4-HNE mediated inhibition of hDDAH-1: implications in no regulation
    Scott P Forbes
    Department of Physiology and Functional Genomics, The University of Florida College of Medicine, Gainesville, Florida 32610, USA
    Biochemistry 47:1819-26. 2008
  10. ncbi Role of DDAH-1 in lipid peroxidation product-mediated inhibition of endothelial NO generation
    ARTHUR J POPE
    Davis Heart and Lung Research Institute, Department of Pharmacology, The Ohio State University College of Medicine, Ohio 43210, USA
    Am J Physiol Cell Physiol 293:C1679-86. 2007

Research Grants

  1. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013

Detail Information

Publications11

  1. ncbi Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular function
    Arturo J Cardounel
    Department of Pharmacology, Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA
    J Biol Chem 282:879-87. 2007
    ..Thus, MAs are critical mediators of vascular dysfunction following vascular injury...
  2. pmc Age and exercise training alter signaling through reactive oxygen species in the endothelium of skeletal muscle arterioles
    Amy L Sindler
    Department of Physiology and Pharmacology, and the Center for Interdisciplinary Research in Cardiovascular Sciences, West Virginia University School of Medicine, Morgantown, West Virginia, USA
    J Appl Physiol (1985) 114:681-93. 2013
    ....
  3. pmc Suppression of eNOS-derived superoxide by caveolin-1: a biopterin-dependent mechanism
    Kanchana Karuppiah
    Department of Anesthesiology, Ohio State University, Columbus, Ohio, USA
    Am J Physiol Heart Circ Physiol 301:H903-11. 2011
    ....
  4. pmc Superoxide induces endothelial nitric-oxide synthase protein thiyl radical formation, a novel mechanism regulating eNOS function and coupling
    Chun An Chen
    Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA
    J Biol Chem 286:29098-107. 2011
    ..Thus, eNOS protein radical formation provides the basis for a mechanism of superoxide-directed regulation of eNOS, involving thiol oxidation, defining a unique pathway for the redox regulation of cardiovascular function...
  5. pmc S-glutathionylation reshapes our understanding of endothelial nitric oxide synthase uncoupling and nitric oxide/reactive oxygen species-mediated signaling
    Jay L Zweier
    1 Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio
    Antioxid Redox Signal 14:1769-75. 2011
    ..Herein, we briefly review the mechanisms of eNOS uncoupling as well as their interrelationships and the evidence for their importance in disease. Antioxid. Redox Signal. 14, 1769-1775...
  6. pmc Role of dimethylarginine dimethylaminohydrolases in the regulation of endothelial nitric oxide production
    ARTHUR J POPE
    Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida 32607, USA
    J Biol Chem 284:35338-47. 2009
    ....
  7. pmc Role of the PRMT-DDAH-ADMA axis in the regulation of endothelial nitric oxide production
    ARTHUR J POPE
    Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, 32607, United States
    Pharmacol Res 60:461-5. 2009
    ....
  8. ncbi Regulation of eNOS-derived superoxide by endogenous methylarginines
    Lawrence J Druhan
    Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA
    Biochemistry 47:7256-63. 2008
    ..These observations have important implications with regard to the therapeutic use of l-arginine and the methylarginine-NOS inhibitors in the treatment of disease...
  9. ncbi Mechanism of 4-HNE mediated inhibition of hDDAH-1: implications in no regulation
    Scott P Forbes
    Department of Physiology and Functional Genomics, The University of Florida College of Medicine, Gainesville, Florida 32610, USA
    Biochemistry 47:1819-26. 2008
    ..Because DDAH is the primary enzyme involved in methylarginine metabolism, the loss of activity of this enzyme would result in impaired NOS activity and reduced NO bioavailability...
  10. ncbi Role of DDAH-1 in lipid peroxidation product-mediated inhibition of endothelial NO generation
    ARTHUR J POPE
    Davis Heart and Lung Research Institute, Department of Pharmacology, The Ohio State University College of Medicine, Ohio 43210, USA
    Am J Physiol Cell Physiol 293:C1679-86. 2007
    ....
  11. ncbi Hyperoxia and transforming growth factor β1 signaling in the post-ischemic mouse heart
    Yuanjing Li
    Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
    Life Sci 92:547-54. 2013
    ..The current study tests the hypothesis that hyperoxia and nitric oxide (NO) regulate TGF-β1 signaling in the post-ischemic myocardium...

Research Grants30

  1. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013
    ..Using novel and state-of-the-art techniques, floxed mice and molecular approaches to gene regulation, we are well-positioned to lead the study of RAGE in the next cycle of this Program. ..