This Article Full Text Full Text (PDF) 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 Rong, J. X. Articles by Fisher, E. A. Search for Related Content PubMed PubMed Citation Articles by Rong, J. X. Articles by Fisher, E. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHOLESTEROL Related Collections Animal models of human disease

(Circulation. 2001;104:2447.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Elevating High-Density Lipoprotein Cholesterol in Apolipoprotein E-Deficient Mice Remodels Advanced Atherosclerotic Lesions by Decreasing Macrophage and Increasing Smooth Muscle Cell Content

James X. Rong, PhD; Jie Li, MD; Ernane D. Reis, MD; Robin P. Choudhury, BM, BCh; Hayes M. Dansky, MD; Valerie I. Elmalem, BS; John T. Fallon, MD, PhD; Jan L. Breslow, MD; Edward A. Fisher, MD, PhD

From the Department of Medicine and the Zena and Michael A. Wiener Cardiovascular Institute (J.X.R., J.L., E.D.R., R.P.C., V.I.E., J.T.F., E.A.F.) and the Department of Surgery (E.D.R.), Mount Sinai School of Medicine; and the Laboratory of Biochemical Genetics and Metabolism, Rockefeller University (H.M.D., J.L.B.), New York, NY.

Correspondence to Dr Edward A. Fisher, Box 1269, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029. E-mail edward.fisher{at}mssm.edu

Background— HDL cholesterol levels are inversely correlated with coronary heart disease risk in humans, and in animal studies, HDL elevation decreases formation and progression of foam-cell lesions. The potential for HDL to affect preexisting advanced atherosclerotic lesions is not known. To approach this issue, we used a novel mouse aortic transplantation model.

Methods and Results— ApoE-deficient (EKO) mice were fed a Western-type diet for 6 months, and thoracic aortic segments containing advanced lesions replaced segments of the abdominal aorta of 4-month-old EKO syngeneic mice not expressing (plasma HDL cholesterol 26 mg/dL) or expressing (HDL 64 mg/dL) a human apoAI (hAI) transgene. Both types of recipients had comparable non-HDL cholesterol levels. Five months after transplantation, mice were killed and grafts analyzed. Compared with lesion area in pretransplant mice (0.14±0.04 mm², mean±SEM), there was progression in the EKO recipients (0.39±0.06 mm², P<0.01). Compared with EKO recipients, hAI/EKO recipients had retarded progression (0.24±0.04 mm², P<0.05). Immunostaining for CD68 and other macrophage-associated proteins, monocyte chemoattractant protein-1, acyl coenzyme A:cholesterol acyltransferase, and tissue factor, in lesions of pretransplant and EKO recipient mice showed abundant macrophages. In contrast, compared with any other group, lesional macrophage area in hAI/EKO mice decreased >80% (P<0.003), and smooth muscle cell content (-actin staining) increased >300% (P<0.006). The decrease in macrophages and increase in smooth muscle cells was primarily in the superficial subendothelial layer.

Conclusions— Increasing HDL cholesterol levels in EKO mice retards progression of advanced atherosclerotic lesions and remodels them to a more stable-appearing phenotype.

Key Words: muscle smooth • remodeling • plaque • lipoproteins

This article has been cited by other articles:

				W. Zhu, S. Saddar, D. Seetharam, K. L. Chambliss, C. Longoria, D. L. Silver, I. S. Yuhanna, P. W. Shaul, and C. Mineo The Scavenger Receptor Class B Type I Adaptor Protein PDZK1 Maintains Endothelial Monolayer Integrity Circ. Res., February 29, 2008; 102(4): 480 - 487. [Abstract] [Full Text] [PDF]

				J. Barlic and P. M. Murphy Chemokine regulation of atherosclerosis J. Leukoc. Biol., August 1, 2007; 82(2): 226 - 236. [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. M S Lee and R. P Choudhury Prospects for atherosclerosis regression through increase in high-density lipoprotein and other emerging therapeutic targets Heart, May 1, 2007; 93(5): 559 - 564. [Abstract] [Full Text] [PDF]

				H. Pei, Y. Wang, T. Miyoshi, Z. Zhang, A. H. Matsumoto, G. A. Helm, G. Tellides, and W. Shi Direct Evidence for a Crucial Role of the Arterial Wall in Control of Atherosclerosis Susceptibility Circulation, November 28, 2006; 114(22): 2382 - 2389. [Abstract] [Full Text] [PDF]

				C. Mineo, H. Deguchi, J. H. Griffin, and P. W. Shaul Endothelial and Antithrombotic Actions of HDL Circ. Res., June 9, 2006; 98(11): 1352 - 1364. [Abstract] [Full Text] [PDF]

				G. S. Getz and C. A. Reardon Diet and Murine Atherosclerosis Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 242 - 249. [Abstract] [Full Text] [PDF]

				D. Seetharam, C. Mineo, A. K. Gormley, L. L. Gibson, W. Vongpatanasin, K. L. Chambliss, L. D. Hahner, M. L. Cummings, R. L. Kitchens, Y. L. Marcel, et al. High-Density Lipoprotein Promotes Endothelial Cell Migration and Reendothelialization via Scavenger Receptor-B Type I Circ. Res., January 6, 2006; 98(1): 63 - 72. [Abstract] [Full Text] [PDF]

				V. L. Sales, G. K. Sukhova, M. A. Lopez-Ilasaca, P. Libby, V. J. Dzau, and R. E. Pratt Angiotensin Type 2 Receptor Is Expressed in Murine Atherosclerotic Lesions and Modulates Lesion Evolution Circulation, November 22, 2005; 112(21): 3328 - 3336. [Abstract] [Full Text] [PDF]

				S. J. Nicholls, B. Cutri, S. G. Worthley, P. Kee, K.-A. Rye, S. Bao, and P. J. Barter Impact of Short-Term Administration of High-Density Lipoproteins and Atorvastatin on Atherosclerosis in Rabbits Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2416 - 2421. [Abstract] [Full Text] [PDF]

				M. L. Gruen, M. R. Plummer, W. Zhang, K. A. Posey, M. Linton, S. Fazio, and A. H. Hasty Persistence of high density lipoprotein particles in obese mice lacking apolipoprotein A-I J. Lipid Res., September 1, 2005; 46(9): 2007 - 2014. [Abstract] [Full Text] [PDF]

				S. J. Nicholls, G. J. Dusting, B. Cutri, S. Bao, G. R. Drummond, K.-A. Rye, and P. J. Barter Reconstituted High-Density Lipoproteins Inhibit the Acute Pro-Oxidant and Proinflammatory Vascular Changes Induced by a Periarterial Collar in Normocholesterolemic Rabbits Circulation, March 29, 2005; 111(12): 1543 - 1550. [Abstract] [Full Text] [PDF]

				P. R. Moreno and V. Fuster New aspects in the pathogenesis of diabetic atherothrombosis J. Am. Coll. Cardiol., December 21, 2004; 44(12): 2293 - 2300. [Abstract] [Full Text] [PDF]

				M. A. McAteer, J. E. Schneider, K. Clarke, S. Neubauer, K. M. Channon, and R. P. Choudhury Quantification and 3D Reconstruction of Atherosclerotic Plaque Components in Apolipoprotein E Knockout Mice Using Ex Vivo High-Resolution MRI Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2384 - 2390. [Abstract] [Full Text] [PDF]

				S. Mussa, T. Prior, N. Alp, K. Wood, K. M. Channon, and D. P. Taggart Duration of action of antispasmodic agents: novel use of a mouse model as an in vivo pharmacological assay Eur. J. Cardiothorac. Surg., November 1, 2004; 26(5): 988 - 994. [Abstract] [Full Text] [PDF]

				P. J. Barter, S. Nicholls, K.-A. Rye, G.M. Anantharamaiah, M. Navab, and A. M. Fogelman Antiinflammatory Properties of HDL Circ. Res., October 15, 2004; 95(8): 764 - 772. [Abstract] [Full Text] [PDF]

				R. P. Choudhury, J. X. Rong, E. Trogan, V. I. Elmalem, H. M. Dansky, J. L. Breslow, J. L. Witztum, J. T. Fallon, and E. A. Fisher High-Density Lipoproteins Retard the Progression of Atherosclerosis and Favorably Remodel Lesions Without Suppressing Indices of Inflammation or Oxidation Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1904 - 1909. [Abstract] [Full Text] [PDF]

				J. Llodra, V. Angeli, J. Liu, E. Trogan, E. A. Fisher, and G. J. Randolph From the Cover: Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques PNAS, August 10, 2004; 101(32): 11779 - 11784. [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]

				M. Pynn, K. Schafer, S. Konstantinides, and M. Halle Exercise Training Reduces Neointimal Growth and Stabilizes Vascular Lesions Developing After Injury in Apolipoprotein E-Deficient Mice Circulation, January 27, 2004; 109(3): 386 - 392. [Abstract] [Full Text] [PDF]

				J. X. Rong, M. Shapiro, E. Trogan, and E. A. Fisher Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading PNAS, November 11, 2003; 100(23): 13531 - 13536. [Abstract] [Full Text] [PDF]

				M. Zabalawi, S. Bhat, T. Loughlin, M. J. Thomas, E. Alexander, M. Cline, B. Bullock, M. Willingham, and M. G. Sorci-Thomas Induction of Fatal Inflammation in LDL Receptor and ApoA-I Double-Knockout Mice Fed Dietary Fat and Cholesterol Am. J. Pathol., September 1, 2003; 163(3): 1201 - 1213. [Abstract] [Full Text] [PDF]

				H. M. Crauwels, C. E. Van Hove, P. Holvoet, A. G. Herman, and H. Bult Plaque-associated endothelial dysfunction in apolipoprotein E-deficient mice on a regular diet. Effect of human apolipoprotein AI Cardiovasc Res, July 1, 2003; 59(1): 189 - 199. [Abstract] [Full Text] [PDF]

				L. M. Belalcazar, A. Merched, B. Carr, K. Oka, K.-H. Chen, L. Pastore, A. Beaudet, and L. Chan Long-Term Stable Expression of Human Apolipoprotein A-I Mediated by Helper-Dependent Adenovirus Gene Transfer Inhibits Atherosclerosis Progression and Remodels Atherosclerotic Plaques in a Mouse Model of Familial Hypercholesterolemia Circulation, June 3, 2003; 107(21): 2726 - 2732. [Abstract] [Full Text] [PDF]

				J. Ou, Z. Ou, D. W. Jones, S. Holzhauer, O. A. Hatoum, A. W. Ackerman, D. W. Weihrauch, D. D. Gutterman, K. Guice, K. T. Oldham, et al. L-4F, an Apolipoprotein A-1 Mimetic, Dramatically Improves Vasodilation in Hypercholesterolemia and Sickle Cell Disease Circulation, May 13, 2003; 107(18): 2337 - 2341. [Abstract] [Full Text] [PDF]

				R. Corti, V. Fuster, and J.J. Badimon Strategy for ensuring a better future for the vessel wall Eur. Heart J. Suppl., February 1, 2002; 4(suppl_A): A31 - A41. [Abstract] [PDF]

				M. Navab, B. J. Van Lenten, S. T. Reddy, and A. M. Fogelman High-Density Lipoprotein and the Dynamics of Atherosclerotic Lesions Circulation, November 13, 2001; 104(20): 2386 - 2387. [Full Text] [PDF]