Abstract

The long term objective of this proposal is to establish Dimethylarginine Dimethylaminohydrolase (DDAH), the enzyme responsible for methylarginine (MA) metabolism, as a key regulator of vascular function and the response to injury. Altered nitric oxide (NO) biosynthesis has been implicated in the pathogenesis of restenosis injury and it appears that accumulation of the endogenous nitric oxide synthase inhibitors, ADMA and NMMA, are responsible for the reduced NO generation observed in these conditions. We have shown that in both rabbit and rat models of balloon- mediated restenosis injury, vascular DDAH expression is significantly decreased with a concomitant increase in cellular MA levels. The overall hypothesis of this proposal is that the loss of DDAH expression/activity results in MA accumulation and decreased NO bioavailabilty with subsequent loss of the anti-proliferative anti-atherogenic properties afforded to the vascular wall by NO. To test this hypothesis we will pursue the following aims.
In aim 1, we will define how modulation of DDAH affects methylarginine levels and subsequent NOS-derived NO and superoxide generation.
In aim 2, we will determine the modulation of DDAH in vascular injury and its role in arterial remodeling. These studies will examine the effects of loss of DDAH expression on smooth muscle cell proliferation, migration and endothelial regeneration. In addition, using an AAV vector carrying the DDAH gene, we will determine whether DDAH over expression can modulate the vascular remodeling process and improve vascular function.
The final aim will determine the role methylarginines in atherogenesis. Because DDAH is regulated by LDL, we will study the effects of DDAH over expression on the initiation and progression of atherosclerosis in the hyperlipidemic state. We believe that this project will establish DDAH as a critical component in the vascular response to injury and may serve as a novel therapeutic target in the treatment of vasculoproliferative disorders.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081734-02
Application #
7208946
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Goldman, Stephen
Project Start
2006-03-15
Project End
2007-06-30
Budget Start
2007-03-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$137,305
Indirect Cost

  Institution

Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210

  Publications

Velayutham, Murugesan; Hemann, Craig F; Cardounel, Arturo J et al. (2016) Sulfite Oxidase Activity of Cytochrome c: Role of Hydrogen Peroxide. Biochem Biophys Rep 5:96-104
Lynch 4th, Thomas L; Sivaguru, Mayandi; Velayutham, Murugesan et al. (2015) Oxidative Stress in Dilated Cardiomyopathy Caused by MYBPC3 Mutation. Oxid Med Cell Longev 2015:424751
Li, Yuanjing; Cai, Ming; Sun, Qinghua et al. (2013) Hyperoxia and transforming growth factor ?1 signaling in the post-ischemic mouse heart. Life Sci 92:547-54
Shenoy, Vinayak; Gjymishka, Altin; Jarajapu, Yagna P et al. (2013) Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. Am J Respir Crit Care Med 187:648-57
Sindler, Amy L; Reyes, Rafael; Chen, Bei et al. (2013) Age and exercise training alter signaling through reactive oxygen species in the endothelium of skeletal muscle arterioles. J Appl Physiol (1985) 114:681-93
Bonilla, Ingrid M; Sridhar, Arun; Nishijima, Yoshinori et al. (2013) Differential effects of the peroxynitrite donor, SIN-1, on atrial and ventricular myocyte electrophysiology. J Cardiovasc Pharmacol 61:401-7
Zweier, Jay L; Chen, Chun-An; Druhan, Lawrence J (2011) S-glutathionylation reshapes our understanding of endothelial nitric oxide synthase uncoupling and nitric oxide/reactive oxygen species-mediated signaling. Antioxid Redox Signal 14:1769-75
Chen, Chun-An; Lin, Cho-Hao; Druhan, Lawrence J et al. (2011) Superoxide induces endothelial nitric-oxide synthase protein thiyl radical formation, a novel mechanism regulating eNOS function and coupling. J Biol Chem 286:29098-107
Karuppiah, Kanchana; Druhan, Lawrence J; Chen, Chun-an et al. (2011) Suppression of eNOS-derived superoxide by caveolin-1: a biopterin-dependent mechanism. Am J Physiol Heart Circ Physiol 301:H903-11
Thomazella, Maria Cristina D; Góes, Marisa F S; Andrade, Cláudia R et al. (2011) Effects of high adherence to mediterranean or low-fat diets in medicated secondary prevention patients. Am J Cardiol 108:1523-9

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