Published Online
on August 5, 2002

A more recent version of this article appeared on August 27, 2002

This Article Full Text (PDF) All Versions of this Article: 106/9/1154    most recent 01.CIR.0000026820.87824.6Av1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Forgione, M. A. Articles by Loscalzo, J. Search for Related Content PubMed Articles by Forgione, M. A. Articles by Loscalzo, J. Related Collections Genetically altered mice Ischemic biology - basic studies Oxidant stress Endothelium/vascular type/nitric oxide

Submitted on April 29, 2002
Revised on May 31, 2002
Accepted on June 3, 2002

Heterozygous Cellular Glutathione Peroxidase Deficiency in the Mouse. Abnormalities in Vascular and Cardiac Function and Structure

Marc A. Forgione MD, Andre Cap PhD, Ronglih Liao PhD, Nicanor I. Moldovan PhD, Robert T. Eberhardt MD, Chee Chew Lim PhD, John Jones MD, Pascal J. Goldschmidt-Clermont MD, and Joseph Loscalzo MD, PhD^*

From Evans Department of Medicine (M.A.F., R.L., R.T.E., C.C.L., J.L.), Department of Surgery (J.J.), and Whitaker Cardiovascular Institute (M.A.F., A.C., R.L., C.C.L., R.T.E., J.J., J.L.), Boston University School of Medicine, Boston, Mass; Cardiology Section, Department of Medicine (N.M.), The Ohio State University, Columbus, Ohio; and Duke University School of Medicine (P.G.), Durham, NC.

^* To whom correspondence should be addressed. E-mail: jloscalz{at}bu.edu.

Background—Oxidant stress has been implicated in the pathogenesis of atherothrombosis and other vascular disorders accompanied by endothelial dysfunction. Glutathione peroxidases (GPx) play an important role in the cellular defense against oxidant stress by utilizing glutathione (GSH) to reduce lipid hydroperoxides and hydrogen peroxide to their corresponding alcohols. Cellular GPx (GPx-1) is the principal intracellular isoform of GPx. We hypothesized that GPx-1 deficiency per se induces endothelial dysfunction and structural vascular abnormalities through increased oxidant stress.

Methods and Results—A murine model of heterozygous deficiency of GPx-1 (GPx^+/-) was investigated to examine this hypothesis. Mesenteric arterioles in GPx-1^+/- mice demonstrated vasoconstriction to acetylcholine compared with vasodilation in wild-type mice (maximal change in vessel diameter, -13.0±2.8% versus 13.2±2.8%, P<0.0001). We also noted an increase in the plasma and aortic levels of the isoprostane iPF₂-III, a marker of oxidant stress, in GPx-1^+/- mice compared with wild-type mice (170.4±23 pg/mL plasma versus 98.7±7.1 pg/mL plasma, P<0.03; 11.7±0.87 pg/mg aortic tissue versus 8.2±0.55 pg/mg aortic tissue, P<0.01). Histological sections from the coronary vasculature of GPx-1^+/- mice show increased perivascular matrix deposition, an increase in the number of adventitial fibroblasts, and intimal thickening. These structural abnormalities in the myocardial vasculature were accompanied by diastolic dysfunction after ischemia-reperfusion.

Conclusions—These findings demonstrate that heterozygous deficiency of GPx-1 leads to endothelial dysfunction, possibly associated with increased oxidant stress, and to significant structural vascular and cardiac abnormalities. These data illustrate the importance of this key antioxidant enzyme in functional and structural responses of the mammalian cardiovascular system.

Key words: endothelium • vasculature • antioxidants • oxygen • nitric oxide

This article has been cited by other articles:

				D. E. Handy, E. Lubos, Y. Yang, J. D. Galbraith, N. Kelly, Y.-Y. Zhang, J. A. Leopold, and J. Loscalzo Glutathione Peroxidase-1 Regulates Mitochondrial Function to Modulate Redox-dependent Cellular Responses J. Biol. Chem., May 1, 2009; 284(18): 11913 - 11921. [Abstract] [Full Text] [PDF]

				W. C. Hawkes and L. J. Laslett Selenium supplementation does not improve vascular responsiveness in healthy North American men Am J Physiol Heart Circ Physiol, February 1, 2009; 296(2): H256 - H262. [Abstract] [Full Text] [PDF]

				J. L. Tarry-Adkins, M. S. Martin-Gronert, J.-H. Chen, R. L. Cripps, and S. E. Ozanne Maternal diet influences DNA damage, aortic telomere length, oxidative stress, and antioxidant defense capacity in rats FASEB J, June 1, 2008; 22(6): 2037 - 2044. [Abstract] [Full Text] [PDF]

				M. Kerkeni, F. Added, M. B. Farhat, A. Miled, F. Trivin, and K. Maaroufi Hyperhomocysteinaemia and parameters of antioxidative defence in Tunisian patients with coronary heart disease Ann Clin Biochem, March 1, 2008; 45(2): 193 - 198. [Abstract] [Full Text] [PDF]

				S. Musaad and E. N. Haynes Biomarkers of Obesity and Subsequent Cardiovascular Events Epidemiol. Rev., May 10, 2007; (2007) mxm005v1. [Abstract] [Full Text] [PDF]

				M. Torzewski, V. Ochsenhirt, A. L. Kleschyov, M. Oelze, A. Daiber, H. Li, H. Rossmann, S. Tsimikas, K. Reifenberg, F. Cheng, et al. Deficiency of Glutathione Peroxidase-1 Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 850 - 857. [Abstract] [Full Text] [PDF]

				Z. Cao, H. Zhu, L. Zhang, X. Zhao, J. L. Zweier, and Y. Li Antioxidants and Phase 2 Enzymes in Cardiomyocytes: Chemical Inducibility and Chemoprotection Against Oxidant and Simulated Ischemia-Reperfusion Injury Experimental Biology and Medicine, September 1, 2006; 231(8): 1353 - 1364. [Abstract] [Full Text] [PDF]

				J. B. de Haan, P. K. Witting, N. Stefanovic, J. Pete, M. Daskalakis, I. Kola, R. Stocker, and J. J. Smolich Lack of the antioxidant glutathione peroxidase-1 does not increase atherosclerosis in C57BL/J6 mice fed a high-fat diet J. Lipid Res., June 1, 2006; 47(6): 1157 - 1167. [Abstract] [Full Text] [PDF]

				N. Ardanaz and P. J. Pagano Hydrogen peroxide as a paracrine vascular mediator: regulation and signaling leading to dysfunction. Experimental Biology and Medicine, March 1, 2006; 231(3): 237 - 251. [Abstract] [Full Text] [PDF]

				J. Haendeler and S. Dimmeler Inseparably Tied: Functional and Antioxidative Capacity of Endothelial Progenitor Cells Circ. Res., February 3, 2006; 98(2): 157 - 158. [Full Text] [PDF]

				G. Galasso, S. Schiekofer, K. Sato, R. Shibata, D. E. Handy, N. Ouchi, J. A. Leopold, J. Loscalzo, and K. Walsh Impaired Angiogenesis in Glutathione Peroxidase-1-Deficient Mice Is Associated With Endothelial Progenitor Cell Dysfunction Circ. Res., February 3, 2006; 98(2): 254 - 261. [Abstract] [Full Text] [PDF]

				J. A. Leopold and J. Loscalzo Oxidative Enzymopathies and Vascular Disease Arterioscler Thromb Vasc Biol, July 1, 2005; 25(7): 1332 - 1340. [Abstract] [Full Text] [PDF]

				R. Schnabel, K. J. Lackner, H. J. Rupprecht, C. Espinola-Klein, M. Torzewski, E. Lubos, C. Bickel, F. Cambien, L. Tiret, T. Munzel, et al. Glutathione Peroxidase-1 and Homocysteine for Cardiovascular Risk Prediction: Results from the AtheroGene Study J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1631 - 1637. [Abstract] [Full Text] [PDF]

				Y. Zhang, D. E. Handy, and J. Loscalzo Adenosine-Dependent Induction of Glutathione Peroxidase 1 in Human Primary Endothelial Cells and Protection Against Oxidative Stress Circ. Res., April 29, 2005; 96(8): 831 - 837. [Abstract] [Full Text] [PDF]

				R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]

				T. Hamanishi, H. Furuta, H. Kato, A. Doi, M. Tamai, H. Shimomura, S. Sakagashira, M. Nishi, H. Sasaki, T. Sanke, et al. Functional Variants in the Glutathione Peroxidase-1 (GPx-1) Gene Are Associated With Increased Intima-Media Thickness of Carotid Arteries and Risk of Macrovascular Diseases in Japanese Type 2 Diabetic Patients Diabetes, September 1, 2004; 53(9): 2455 - 2460. [Abstract] [Full Text] [PDF]

				G. Y. Oudit, M. G. Trivieri, N. Khaper, T. Husain, G. J. Wilson, P. Liu, M. J. Sole, and P. H. Backx Taurine Supplementation Reduces Oxidative Stress and Improves Cardiovascular Function in an Iron-Overload Murine Model Circulation, April 20, 2004; 109(15): 1877 - 1885. [Abstract] [Full Text] [PDF]

				M. Jain, L. Cui, D. A. Brenner, B. Wang, D. E. Handy, J. A. Leopold, J. Loscalzo, C. S. Apstein, and R. Liao Increased Myocardial Dysfunction After Ischemia-Reperfusion in Mice Lacking Glucose-6-Phosphate Dehydrogenase Circulation, February 24, 2004; 109(7): 898 - 903. [Abstract] [Full Text] [PDF]

				Y. Taniyama and K. K. Griendling Reactive Oxygen Species in the Vasculature: Molecular and Cellular Mechanisms Hypertension, December 1, 2003; 42(6): 1075 - 1081. [Abstract] [Full Text] [PDF]

				S. Blankenberg, H. J. Rupprecht, C. Bickel, M. Torzewski, G. Hafner, L. Tiret, M. Smieja, F. Cambien, J. Meyer, K. J. Lackner, et al. Glutathione Peroxidase 1 Activity and Cardiovascular Events in Patients with Coronary Artery Disease N. Engl. J. Med., October 23, 2003; 349(17): 1605 - 1613. [Abstract] [Full Text] [PDF]

				H. Miura, J. J. Bosnjak, G. Ning, T. Saito, M. Miura, and D. D. Gutterman Role for Hydrogen Peroxide in Flow-Induced Dilation of Human Coronary Arterioles Circ. Res., February 7, 2003; 92 (2): e31 - e40. [Abstract] [Full Text] [PDF]