Published online before print April 18, 2002, doi: 10.1161/01.RES.0000018422.31717.EE
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© 2002 American Heart Association, Inc.
Integrative Physiology |
Recombinant Apolipoprotein A-IMilano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks
From the Department of Pharmacological Sciences (G.C., E.M., M.M., G.F., C.R.S.), University of Milano; Bracco S.p.A (P.L., M.L., V.L.); Columbus Clinic and San Raffaele Hospital (C.D.M., E.K.), Milano, Italy; and Esperion Therapeutics (R.S.N., C.L.B.), Ann Arbor, Mich.
Correspondence to Giulia Chiesa, Dept of Pharmacological Sciences, University of Milano, via Balzaretti 9, 20133 Milano, Italy. E-mail Giulia.Chiesa{at}unimi.it
Apolipoprotein A-IMilano (AIM), a natural variant of human apolipoprotein A-I, confers to carriers a significant protection against vascular disease. In previous studies, administration of recombinant AIM-phospholipid (AIM-PL) complexes to hypercholesterolemic rabbits markedly inhibited neointimal formation after arterial injury; moreover, repeated injections of AIM-PL in apoE-deficient mice significantly reduced atherosclerosis progression. The objective of the present study was to determine if a single localized infusion of AIM-PL complexes administered directly to atheromatous lesions could promote plaque regression. Lipid-rich, atheromatous plaques were generated at both common carotid arteries of 25 rabbits by applying a perivascular electric injury, followed by 1.5% cholesterol diet for 90 days. Rabbits were infused with either saline, phospholipid vesicles, or 3 different AIM-PL doses (250, 500, or 1000 mg of protein) delivered through an intravascular ultrasound (IVUS) catheter positioned at the origin of the right carotid. The lesions at the left carotid artery were therefore exposed to the agents systemically. Infusion of AIM-PL at the 2 highest doses caused reduction of right carotid artery plaque area by the end a 90-minute infusion as assessed by IVUS analysis. Plaque area regression was confirmed by histology in carotid arteries receiving direct (500 and 1000 mg doses) and systemic (500 mg dose) delivery, 72 hours after the start of the treatment. Plaque lipid content was associated with significant and similar decreases in Oil Red O staining in both arteries. These results suggest AIM-PL complexes enhanced lipid removal from arteries is the mechanism responsible for the observed plaque changes.
Key Words: rabbit • lipid-rich plaques • apolipoprotein A-IMilano • regression
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