This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed 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 Ma, X. L. Articles by Yue, T.-L. Search for Related Content PubMed PubMed Citation Articles by Ma, X. L. Articles by Yue, T.-L. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cholesterol Hazardous Substances DB NITRIC OXIDE

(Circulation Research. 1997;80:894-901.)
© 1997 American Heart Association, Inc.

Articles

Hypercholesterolemia Impairs a Detoxification Mechanism Against Peroxynitrite and Renders the Vascular Tissue More Susceptible to Oxidative Injury

Xin L. Ma, Bernard L. Lopez, Gao-Lin Liu, Theodore A. Christopher, Feng Gao, Yaping Guo, Giora Z. Feuerstein, Robert R. Ruffolo, Jr, Frank C. Barone, , Tian-Li Yue

From the Division of Emergency Medicine (X.L.M., B.L.L., G.-L.L., T.A.C., F.G., Y.G.), Thomas Jefferson University, Philadelphia, Pa, and the Department of Cardiovascular Pharmacology (G.Z.F., R.R.R., F.C.B., T.-L.Y.), SmithKline Beecham Pharmaceuticals, King of Prussia, Pa.

Correspondence to Xin L. Ma, MD, PhD, Division of Emergency Medicine, Jefferson Medical College, 1020 Sansom St, Philadelphia, PA 19107-5004. E-mail MA1{at}JEFLIN.TJU.EDU

Abstract Previous studies have shown that glutathione (GSH) plays a central role in the protection against peroxynitrite (ONOO^-) toxicity. The present study evaluated the changes of the GSH cytoprotective system against ONOO^- in hypercholesterolemia and determined the effects of carvedilol, a ß-blocker with free radical–scavenging activity, on these hypercholesterol-induced changes. New Zealand White rabbits were fed either a normal diet, a high-cholesterol diet, or a high-cholesterol diet supplemented with either carvedilol or propranolol. Eight weeks later, the rabbits were killed, and the thoracic aortas were isolated. Total GSH content of aortic tissue, vasorelaxation response of aortic rings to exogenous ONOO^-, ^·NO regeneration from ONOO^- by aortic homogenate, and ONOO^--induced aortic tissue injury were examined. Hypercholesterolemia decreased tissue GSH content (0.52±0.08 versus 0.86±0.04 µmol/g in control, P<.01), attenuated the vasorelaxation response to ONOO^- (40±4.1% versus 76±3.2%, P<.01), reduced ^·NO regeneration from ONOO^- (387±40 versus 662±51 pmol, P<.01), and potentiated ONOO^--induced vascular tissue injury (37±4.4% versus 14±2.6% of increase in lactate dehydrogenase release after 3-morpholinosydnonimine exposure, P<.01). Treatment of the hypercholesterolemic rabbits with carvedilol, but not propranolol, significantly preserved tissue GSH content (0.79±0.05 µmol/g, P<.01 versus nontreated hypercholesterolemic rabbits), restored the vasorelaxation to ONOO^- (61±2%, P<.01), increased ^·NO regeneration from ONOO^- (583±39 pmol, P<.01), and attenuated ONOO^--induced tissue injury (19±1.8%, P<.01). These results suggest that hypercholesterolemia impairs the GSH-mediated detoxification mechanism against ONOO^- and renders the vascular tissue more susceptible to oxidative injury. Carvedilol, a novel vasodilating ß-blocker with antioxidant activity, significantly preserved this self-defense system and protected tissue from oxidant injury.

Key Words: free radical • atherosclerosis • glutathione • tissue injury

This article has been cited by other articles:

				E. Osto, C. M. Matter, A. Kouroedov, T. Malinski, M. Bachschmid, G. G. Camici, U. Kilic, T. Stallmach, J. Boren, S. Iliceto, et al. c-Jun N-Terminal Kinase 2 Deficiency Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction and Oxidative Stress Circulation, November 11, 2008; 118(20): 2073 - 2080. [Abstract] [Full Text] [PDF]

				R. Li, W.-Q. Wang, H. Zhang, X. Yang, Q. Fan, T. A. Christopher, B. L. Lopez, L. Tao, B. J. Goldstein, F. Gao, et al. Adiponectin improves endothelial function in hyperlipidemic rats by reducing oxidative/nitrative stress and differential regulation of eNOS/iNOS activity Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1703 - E1708. [Abstract] [Full Text] [PDF]

				J. Vinten-Johansen Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury Cardiovasc Res, February 15, 2004; 61(3): 481 - 497. [Abstract] [Full Text] [PDF]

				J. H. Indik, S. Goldman, and M. A. Gaballa Oxidative stress contributes to vascular endothelial dysfunction in heart failure Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1767 - H1770. [Abstract] [Full Text] [PDF]

				X.-L. Ma, F. Gao, A. H. Nelson, B. L. Lopez, T. A. Christopher, T.-L. Yue, and F. C. Barone Oxidative Inactivation of Nitric Oxide and Endothelial Dysfunction in Stroke-Prone Spontaneous Hypertensive Rats J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 879 - 885. [Abstract] [Full Text]

				Z. Chen, K. W. Woodburn, C. Shi, D. C. Adelman, C. Rogers, and D. I. Simon Photodynamic Therapy With Motexafin Lutetium Induces Redox-Sensitive Apoptosis of Vascular Cells Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 759 - 764. [Abstract] [Full Text] [PDF]

				X. L. Ma, F. Gao, C.-L. Yao, J. Chen, B. L. Lopez, T. A. Christopher, J. Disa, J.-L. Gu, E. H. Ohlstein, and T.-L. Yue Nitric Oxide Stimulatory and Endothelial Protective Effects of Idoxifene, a Selective Estrogen Receptor Modulator, in the Splanchnic Artery of the Ovariectomized Rat J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 786 - 792. [Abstract] [Full Text]

				B. J. Buckley and A. R. Whorton Adaptive responses to peroxynitrite: increased glutathione levels and cystine uptake in vascular cells Am J Physiol Cell Physiol, October 1, 2000; 279(4): C1168 - C1176. [Abstract] [Full Text] [PDF]

				R. P. Patel, A.-L. Levonen, J. H. Crawford, and V. M. Darley-Usmar Mechanisms of the pro- and anti-oxidant actions of nitric oxide in atherosclerosis Cardiovasc Res, August 18, 2000; 47(3): 465 - 474. [Abstract] [Full Text] [PDF]

				F. Gao, T. A. Christopher, B. L. Lopez, E. Friedman, G. Cai, and X. L. Ma Mechanism of decreased adenosine protection in reperfusion injury of aging rats Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H329 - H338. [Abstract] [Full Text] [PDF]

				X.-L. Ma, F. Gao, B. L. Lopez, T. A. Christopher, and J. Vinten-Johansen Peroxynitrite, a Two-Edged Sword in Post-Ischemic Myocardial Injury---Dichotomy of Action in Crystalloid- Versus Blood-Perfused Hearts J. Pharmacol. Exp. Ther., March 1, 2000; 292(3): 912 - 920. [Abstract] [Full Text]

				R. S Ronson, M. Nakamura, and J. Vinten-Johansen The cardiovascular effects and implications of peroxynitrite Cardiovasc Res, October 1, 1999; 44(1): 47 - 59. [Abstract] [Full Text] [PDF]

				J. F. KEANEY JR., D. I. SIMON, and J. E. FREEDMAN Vitamin E and vascular homeostasis: implications for atherosclerosis FASEB J, June 1, 1999; 13(9): 965 - 975. [Abstract] [Full Text]

				M. de Lorgeril Dietary arginine and the prevention of cardiovascular diseases Cardiovasc Res, March 1, 1998; 37(3): 560 - 563. [Full Text] [PDF]

				R. M. F. Wever, T. F. Luscher, F. Cosentino, and T. J. Rabelink Atherosclerosis and the Two Faces of Endothelial Nitric Oxide Synthase Circulation, January 13, 1998; 97(1): 108 - 112. [Full Text] [PDF]

				W. Shi, X. Wang, D. M. Shih, V. E. Laubach, M. Navab, and A. J. Lusis Paradoxical Reduction of Fatty Streak Formation in Mice Lacking Endothelial Nitric Oxide Synthase Circulation, April 30, 2002; 105(17): 2078 - 2082. [Abstract] [Full Text] [PDF]