Methylarginines and Vascular Injury
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
- Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular functionArturo 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...
- Age and exercise training alter signaling through reactive oxygen species in the endothelium of skeletal muscle arteriolesAmy 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....
- Suppression of eNOS-derived superoxide by caveolin-1: a biopterin-dependent mechanismKanchana Karuppiah
Department of Anesthesiology, Ohio State University, Columbus, Ohio, USA
Am J Physiol Heart Circ Physiol 301:H903-11. 2011....
- Superoxide induces endothelial nitric-oxide synthase protein thiyl radical formation, a novel mechanism regulating eNOS function and couplingChun 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...
- S-glutathionylation reshapes our understanding of endothelial nitric oxide synthase uncoupling and nitric oxide/reactive oxygen species-mediated signalingJay 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...
- Role of dimethylarginine dimethylaminohydrolases in the regulation of endothelial nitric oxide productionARTHUR 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....
- Role of the PRMT-DDAH-ADMA axis in the regulation of endothelial nitric oxide productionARTHUR J POPE
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, 32607, United States
Pharmacol Res 60:461-5. 2009....
- Regulation of eNOS-derived superoxide by endogenous methylargininesLawrence 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...
- Mechanism of 4-HNE mediated inhibition of hDDAH-1: implications in no regulationScott 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...
- Role of DDAH-1 in lipid peroxidation product-mediated inhibition of endothelial NO generationARTHUR 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....
- Hyperoxia and transforming growth factor β1 signaling in the post-ischemic mouse heartYuanjing 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...
- RAGE and Mechanisms of Vascular DysfunctionShi 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. ..