This Article Full Text Full Text (PDF) All Versions of this Article: 105/12/1485    most recent 01.CIR.0000012142.69612.25v1 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 Nakata, Y. Articles by Maeda, N. Search for Related Content PubMed PubMed Citation Articles by Nakata, Y. Articles by Maeda, N. Related Collections Nutrition Oxidant stress Animal models of human disease Risk Factors Genetically altered mice

(Circulation. 2002;105:1485.)
© 2002 American Heart Association, Inc.

Vulnerable Atherosclerotic Plaque Morphology in Apolipoprotein E–Deficient Mice Unable to Make Ascorbic Acid

From the Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC.

Correspondence to Dr Nobuyo Maeda, Department of Pathology and Laboratory Medicine, 710 Brinkhous-Bullitt Building, University of North Carolina, Chapel Hill, NC 27599-7125. E-mail nobuyo{at}med.unc.edu

Background— Oxidative stress is thought to play an important role in atherogenesis, suggesting that antioxidants could prevent coronary artery disease. However, the efficacy of vitamin C in reducing atherosclerosis is debatable in humans and has not been tested rigorously in animals.

Methods and Results— Gulo^-/-Apoe^-/- mice were used to test a hypothesis that chronic vitamin C deficiency enhances the initiation and development of atherosclerosis. These mice are dependent on dietary vitamin C because of the lack of L-gulonolactone--oxidase and are prone to develop atherosclerosis because of lacking apolipoprotein E. Beginning at 6 weeks of age, the Gulo^-/-Apoe^-/- mice were fed regular chow or Western-type diets containing high fat and supplemented with either 0.033 g or 3.3 g/L of vitamin C in their drinking water. This regimen produced mice with chronically low vitamin C (average 1.5 µg/mL in plasma) or high vitamin C (average 10 to 30 µg/mL in plasma). Morphometric analysis showed that within each sex, age, and diet group, the sizes of the atherosclerotic plaques were not different between low vitamin C mice and high vitamin C mice. However, advanced plaques in the low vitamin C mice had significantly reduced amounts of Sirius red–staining collagen (36.4±2.2% versus 54.8±2.3%, P<0.0001), larger necrotic cores within the plaques, and reduced fibroproliferation and neovascularization in the aortic adventitia.

Conclusions— Chronic vitamin C deficiency does not influence the initiation or progression of atherosclerotic plaques but severely compromises collagen deposition and induces a type of plaque morphology that is potentially vulnerable to rupture.

Key Words: antioxidants • atherosclerosis • collagen • plaque rupture • vitamin C

This article has been cited by other articles:

				Y. Li and H. E. Schellhorn New Developments and Novel Therapeutic Perspectives for Vitamin C J. Nutr., October 1, 2007; 137(10): 2171 - 2184. [Abstract] [Full Text] [PDF]

				T. Fukai Endothelial GTPCH in eNOS Uncoupling and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., July 1, 2007; 27(7): 1493 - 1495. [Full Text] [PDF]

				T. Takaya, K.-i. Hirata, T. Yamashita, M. Shinohara, N. Sasaki, N. Inoue, T. Yada, M. Goto, A. Fukatsu, T. Hayashi, et al. A Specific Role for eNOS-Derived Reactive Oxygen Species in Atherosclerosis Progression Arterioscler. Thromb. Vasc. Biol., July 1, 2007; 27(7): 1632 - 1637. [Abstract] [Full Text] [PDF]

				W. Hsueh, E. D. Abel, J. L. Breslow, N. Maeda, R. C. Davis, E. A. Fisher, H. Dansky, D. A. McClain, R. McIndoe, M. K. Wassef, et al. Recipes for Creating Animal Models of Diabetic Cardiovascular Disease Circ. Res., May 25, 2007; 100(10): 1415 - 1427. [Abstract] [Full Text] [PDF]

				J. D. Chang, G. K. Sukhova, P. Libby, E. Schvartz, A. H. Lichtenstein, S. J. Field, C. Kennedy, S. Madhavarapu, J. Luo, D. Wu, et al. Deletion of the phosphoinositide 3-kinase p110{gamma} gene attenuates murine atherosclerosis PNAS, May 8, 2007; 104(19): 8077 - 8082. [Abstract] [Full Text] [PDF]

				P. Secchiero, R. Candido, F. Corallini, S. Zacchigna, B. Toffoli, E. Rimondi, B. Fabris, M. Giacca, and G. Zauli Systemic Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Delivery Shows Antiatherosclerotic Activity in Apolipoprotein E-Null Diabetic Mice Circulation, October 3, 2006; 114(14): 1522 - 1530. [Abstract] [Full Text] [PDF]

				K. K. Parsons, N. Maeda, M. Yamauchi, A. J. Banes, and B. H. Koller Ascorbic acid-independent synthesis of collagen in mice Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1131 - E1139. [Abstract] [Full Text] [PDF]

				W.A. Boisvert, D.M. Rose, A. Boullier, O. Quehenberger, A. Sydlaske, K.A Johnson, L.K. Curtiss, and R. Terkeltaub Leukocyte Transglutaminase 2 Expression Limits Atherosclerotic Lesion Size Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 563 - 569. [Abstract] [Full Text] [PDF]

				Y. V. Bobryshev, I. F. Charo, and A. M. Aslanian Natural Killer T Cells in Atherosclerosis Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): e40 - e40. [Full Text] [PDF]

				J. Johnson, K. Carson, H. Williams, S. Karanam, A. Newby, G. Angelini, S. George, and C. Jackson Plaque Rupture After Short Periods of Fat Feeding in the Apolipoprotein E-Knockout Mouse: Model Characterization and Effects of Pravastatin Treatment Circulation, March 22, 2005; 111(11): 1422 - 1430. [Abstract] [Full Text] [PDF]

				C. Napoli, S. Williams-Ignarro, F. de Nigris, L. O. Lerman, L. Rossi, C. Guarino, G. Mansueto, F. Di Tuoro, O. Pignalosa, G. De Rosa, et al. Long-term combined beneficial effects of physical training and metabolic treatment on atherosclerosis in hypercholesterolemic mice PNAS, June 8, 2004; 101(23): 8797 - 8802. [Abstract] [Full Text] [PDF]

				K. S. Meir and E. Leitersdorf Atherosclerosis in the Apolipoprotein E-Deficient Mouse: A Decade of Progress Arterioscler. Thromb. Vasc. Biol., June 1, 2004; 24(6): 1006 - 1014. [Abstract] [Full Text] [PDF]

				A. Lafont Basic aspects of plaque vulnerability Heart, October 1, 2003; 89(10): 1262 - 1267. [Full Text] [PDF]

				R. W. Saeed, T. Peng, and C. N. Metz Ascorbic Acid Blocks the Growth Inhibitory Effect of Tumor Necrosis Factor-{alpha} on Endothelial Cells Experimental Biology and Medicine, July 1, 2003; 228(7): 855 - 865. [Abstract] [Full Text] [PDF]

				P. Stenvinkel, R. Pecoits-Filho, and B. Lindholm Coronary Artery Disease in End-Stage Renal Disease: No Longer a Simple Plumbing Problem J. Am. Soc. Nephrol., July 1, 2003; 14(7): 1927 - 1939. [Full Text] [PDF]

				W. Palinski and C. Napoli Unraveling Pleiotropic Effects of Statins on Plaque Rupture Arterioscler. Thromb. Vasc. Biol., November 1, 2002; 22(11): 1745 - 1750. [Full Text] [PDF]

				P. Libby and M. Aikawa Vitamin C, Collagen, and Cracks in the Plaque Circulation, March 26, 2002; 105(12): 1396 - 1398. [Full Text] [PDF]