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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2416.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Impact of Short-Term Administration of High-Density Lipoproteins and Atorvastatin on Atherosclerosis in Rabbits

Stephen J. Nicholls; Belinda Cutri; Stephen G. Worthley; Patrick Kee; Kerry-Anne Rye; Shisan Bao; Philip J. Barter

From The Heart Research Institute (S.J.N., B.C., K.-A.R., P.J.B.), Sydney, Australia; Department of Medicine (S.J.N., S.G.W.), University of Adelaide, Australia; Cardiovascular Investigation Unit (S.G.W., P.K.), Royal Adelaide Hospital, Australia; Department of Medicine (K.-A.R., P.J.B.), University of Sydney, Australia; Department of Medicine (K.-A.R.) University of Melbourne, Australia; Department of Pathology (S.B.), University of Sydney, Australia.

Correspondence to Philip J. Barter, The Heart Research Institute, 145 Missenden Rd, Camperdown, NSW 2050 Australia. E-mail p.barter{at}hri.org.au

Objective— This study investigates effects of short-term administration of high-density lipoproteins (HDL) and a statin on atherosclerosis in cholesterol-fed rabbits. Effects of HDL apolipoprotein and phospholipid composition have also been investigated.

Methods and Results— Aortic atherosclerosis was established over 17 weeks in 46 rabbits by balloon denudation and cholesterol feeding. During the past 5 days of the cholesterol-feeding period, animals received: (1) no treatment; (2) oral atorvastatin 5 mg/kg on each of the 5 days; or (3) infusions of HDL (8 mg/kg apolipoprotein A-I) on days 1 and 3 of the treatment phase. After euthanization, lesion size and composition were assessed by histological and immunohistochemical analysis. HDL (but not atorvastatin) reduced lesion size by 36% (P<0.05). The ratio of smooth muscle cells to macrophages in the lesions increased 2.6-fold in animals infused with HDL (P<0.05) and 4-fold in those receiving atorvastatin (P<0.01). HDL and atorvastatin reduced matrix metalloproteinase (MMP)-9 expression by 42% (P<0.05) and 45% (P<0.03), respectively. HDL increased thrombomodulin expression 2-fold (P<0.03). The beneficial effects on lesion area and plaque cellular composition were influenced by HDL phospholipid and apolipoprotein composition.

Conclusion— Infusing small amounts of HDL rapidly reduces lesion size and is comparable to atorvastatin in promoting a stable plaque phenotype.

Atherosclerosis was established in rabbit aortas by balloon denudation and 17 weeks of cholesterol feeding. Infusing HDL during the last 5 days reduced lesion size, increased the ratio of smooth muscle cells to macrophages, and reduced metalloproteinase while increasing thrombomodulin expression in the lesions, consistent with stabilization of plaques by HDL.

Key Words: atherosclerosis • high-density lipoprotein • inflammation • lipoproteins • plaque stabilization

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