(Circulation. 2001;103:1282.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Endothelial Regulation of Vasomotion in ApoE-Deficient Mice
Implications for Interactions Between Peroxynitrite and Tetrahydrobiopterin
From the Department of Medicine, Emory University School of Medicine, and Veterans Administration Hospital, Atlanta, Ga (J.B.L., M.S., S.K., L.M., A.W., T.F., D.G.H.); the Department of Anesthesia, University of Alabama, Birmingham (B.A.F., M.T.); and Medical Department B, Division of Cardiology, Rigshospitalet, Denmark (J.B.L.).
Correspondence to David G. Harrison, Professor of Medicine, Emory University School of Medicine, Cardiology Department, 1639 Pierce Dr, WMB-319, Atlanta, GA 30322. E-mail dharr02{at}emory.edu
Background—Altered endothelial cell nitric oxide (NO·) production in atherosclerosis may be due to a reduction of intracellular tetrahydrobiopterin, which is a critical cofactor for NO synthase (NOS). In addition, previous literature suggests that inactivation of NO· by increased vascular production superoxide (O2·-) also reduces NO· bioactivity in several disease states. We sought to determine whether these 2 seemingly disparate mechanisms were related.
Methods and Results—Endothelium-dependent vasodilation was abnormal in aortas of apoE-deficient (apoE-/-) mice, whereas vascular superoxide production (assessed by 5 µmol/L lucigenin) was markedly increased. Treatment with either liposome-entrapped superoxide dismutase or sepiapterin, a precursor to tetrahydrobiopterin, improved endothelium-dependent vasodilation in aortas from apoE-/- mice. Hydrogen peroxide had no effect on the decay of tetrahydrobiopterin, as monitored spectrophotometrically. In contrast, superoxide modestly and peroxynitrite strikingly increased the decay of tetrahydrobiopterin over 500 seconds. Luminol chemiluminescence, inhibitable by the peroxynitrite scavengers ebselen and uric acid, was markedly increased in apoE-/- aortic rings. In vessels from apoE-/- mice, uric acid improved endothelium-dependent relaxation while having no effect in vessels from control mice. Treatment of normal aortas with exogenous peroxynitrite dramatically increased vascular O2·- production, seemingly from eNOS, because this effect was absent in vessels lacking endothelium, was blocked by NOS inhibition, and did not occur in vessels from mice lacking eNOS.
Conclusions—Reactive oxygen species may alter endothelium-dependent vascular relaxation not only by the interaction of O2·- with NO· but also through interactions between peroxynitrite and tetrahydrobiopterin. Peroxynitrite oxidation of tetrahydrobiopterin may represent a pathogenic cause of "uncoupling" of NO synthase.
Key Words: endothelium • genes • vessels
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K. A. Blackwell, J. P. Sorenson, D. M. Richardson, L. A. Smith, O. Suda, K. Nath, and Z. S. Katusic Mechanisms of aging-induced impairment of endothelium-dependent relaxation: role of tetrahydrobiopterin Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2448 - H2453. [Abstract] [Full Text] [PDF]
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S. Wassmann, T. Czech, M. van Eickels, I. Fleming, M. Bohm, and G. Nickenig Inhibition of Diet-Induced Atherosclerosis and Endothelial Dysfunction in Apolipoprotein E/Angiotensin II Type 1A Receptor Double-Knockout Mice Circulation, November 9, 2004; 110(19): 3062 - 3067. [Abstract] [Full Text] [PDF]
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J.-M. Li and A. M Shah Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2004; 287(5): R1014 - R1030. [Abstract] [Full Text] [PDF]
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F. M. Faraci and S. P. Didion Vascular Protection: Superoxide Dismutase Isoforms in the Vessel Wall Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1367 - 1373. [Abstract] [Full Text] [PDF]
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M. d. C. P. Franco, Z. B. Fortes, E. H. Akamine, E. M. Kawamoto, C. Scavone, L. R. G. de Britto, M. N. Muscara, S. A. Teixeira, R. C. A. Tostes, M. H. C. Carvalho, et al. Tetrahydrobiopterin improves endothelial dysfunction and vascular oxidative stress in microvessels of intrauterine undernourished rats J. Physiol., July 1, 2004; 558(1): 239 - 248. [Abstract] [Full Text] [PDF]
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S. Kawashima and M. Yokoyama Dysfunction of Endothelial Nitric Oxide Synthase and Atherosclerosis Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 998 - 1005. [Abstract] [Full Text] [PDF]
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U. Landmesser, B. Hornig, and H. Drexler Endothelial Function: A Critical Determinant in Atherosclerosis? Circulation, June 1, 2004; 109(21_suppl_1): II-27 - II-33. [Abstract] [Full Text] [PDF]
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J. M. Sasser, J. C. Sullivan, A. A. Elmarakby, B. E. Kemp, D. M. Pollock, and J. S. Pollock Reduced NOS3 Phosphorylation Mediates Reduced NO/cGMP Signaling in Mesenteric Arteries of Deoxycorticosterone Acetate-Salt Hypertensive Rats Hypertension, May 1, 2004; 43(5): 1080 - 1085. [Abstract] [Full Text] [PDF]
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O. Jung, J.G. Schreiber, H. Geiger, T. Pedrazzini, R. Busse, and R.P. Brandes gp91phox-Containing NADPH Oxidase Mediates Endothelial Dysfunction in Renovascular Hypertension Circulation, April 13, 2004; 109(14): 1795 - 1801. [Abstract] [Full Text] [PDF]
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N. J. Alp and K. M. Channon Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 413 - 420. [Abstract] [Full Text]
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N. J. Alp, M. A. McAteer, J. Khoo, R. P. Choudhury, and K. M. Channon Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 445 - 450. [Abstract] [Full Text]
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S. O. Hynes, L. A. Smith, D. M. Richardson, I. Kovesdi, T. O'Brien, and Z. S. Katusic In vivo expression and function of recombinant GTPCH I in the rabbit carotid artery Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H570 - H574. [Abstract] [Full Text] [PDF]
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J. Zhu, T. Mori, T. Huang, and J. H. Lombard Effect of high-salt diet on NO release and superoxide production in rat aorta Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H575 - H583. [Abstract] [Full Text] [PDF]
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J. A. Beckman, A. B. Goldfine, M. B. Gordon, L. A. Garrett, J. F. Keaney Jr., and M. A. Creager Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2392 - H2398. [Abstract] [Full Text] [PDF]
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U. Hink, M. Oelze, P. Kolb, M. Bachschmid, M.-H. Zou, A. Daiber, H. Mollnau, M. August, S. Baldus, N. Tsilimingas, et al. Role for peroxynitrite in the inhibition of prostacyclin synthase in nitrate tolerance J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1826 - 1834. [Abstract] [Full Text] [PDF]
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T. Munzel, R. Feil, A. Mulsch, S. M. Lohmann, F. Hofmann, and U. Walter Physiology and Pathophysiology of Vascular Signaling Controlled by Cyclic Guanosine 3',5'-Cyclic Monophosphate-Dependent Protein Kinase Circulation, November 4, 2003; 108(18): 2172 - 2183. [Full Text] [PDF]
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K. K. Griendling and G. A. FitzGerald Oxidative Stress and Cardiovascular Injury: Part II: Animal and Human Studies Circulation, October 28, 2003; 108(17): 2034 - 2040. [Full Text] [PDF]
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T. Mori and A. W. Cowley Jr Angiotensin II-NAD(P)H Oxidase-Stimulated Superoxide Modifies Tubulovascular Nitric Oxide Cross-Talk in Renal Outer Medulla Hypertension, October 1, 2003; 42(4): 588 - 593. [Abstract] [Full Text] [PDF]
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M. A. Creager, T. F. Luscher, F. Cosentino, and J. A. Beckman Diabetes and Vascular Disease: Pathophysiology, Clinical Consequences, and Medical Therapy: Part I Circulation, September 23, 2003; 108(12): 1527 - 1532. [Full Text] [PDF]
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J.-S. Zheng, X.-Q. Yang, K. J. Lookingland, G. D. Fink, C. Hesslinger, G. Kapatos, I. Kovesdi, and A. F. Chen Gene Transfer of Human Guanosine 5'-Triphosphate Cyclohydrolase I Restores Vascular Tetrahydrobiopterin Level and Endothelial Function in Low Renin Hypertension Circulation, September 9, 2003; 108(10): 1238 - 1245. [Abstract] [Full Text] [PDF]
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X. Gu, A. B. El-Remessy, S. E. Brooks, M. Al-Shabrawey, N.-T. Tsai, and R. B. Caldwell Hyperoxia induces retinal vascular endothelial cell apoptosis through formation of peroxynitrite Am J Physiol Cell Physiol, September 1, 2003; 285(3): C546 - C554. [Abstract] [Full Text] [PDF]
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N. Ihlemann, C. Rask-Madsen, A. Perner, H. Dominguez, T. Hermann, L. Kober, and C. Torp-Pedersen Tetrahydrobiopterin restores endothelial dysfunction induced by an oral glucose challenge in healthy subjects Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H875 - H882. [Abstract] [Full Text] [PDF]
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