© 1999 American Heart Association, Inc.
Original Contributions |
Inhibition of Arterial Thrombus Formation by ApoA1 Milano
From the Departments of Medicine (D.L., S.W., B.Y., W.W.N., J.L.M.) and Pathology (D.S.Z., S.K.), University of Florida College of Medicine; the VA Medical Center (D.L., S.W., B.Y., D.S.Z., W.W.N., J.L.M.), Gainesville, Florida; and the Department of Forensic Medicine (T.S.), University of Uppsala, Uppsala, Sweden.
Correspondence to J.L. Mehta, MD, PhD, Department of Medicine, University of Florida, College of Medicine, Box 100277, JHMHC, Gainesville, Florida 32610. E-mail mehta{at}medmac.ufl.edu
Abstract—The mutant form of human apoA1, known as apoA1 Milano, is formed as a result of arginine 173 to cysteine substitution and inhibits experimental atherosclerosis in cholesterol-fed animals. This study was designed to determine if apoA1 Milano would modify arterial thrombogenesis. Sprague Dawley rats were intravenously administered the carrier alone (n=8) or apoA1 Milano (20 mg · kg-1 · d-1 for 4 to 10 days, n=17). The abdominal cavity was opened, and the abdominal aorta was isolated. Whatman paper impregnated with 35% FeCl3 was wrapped around the surface of the aorta, and aortic flow was recorded continuously. In carrier-treated rats, an occlusive platelet-fibrin-rich thrombus was formed in 21.2±4.1 (mean±SD) minutes. Treatment of rats with apoA1 Milano markedly delayed time to thrombus formation (38.8±11.9 versus 21.2±4.1 minutes, P<0.01), inhibited platelet aggregation (25±7% versus 50±11%, P<0.01), and reduced weight of the thrombus (18.5±1.8 versus 23.7±2.3 mg/cm, P<0.01). Total cholesterol and HDL levels remained similar in both groups of rats, but plasma apoA1 Milano levels were elevated in apoA1 Milano–treated rats. In in vitro studies, incubation of platelets with apoA1 Milano reduced ADP-induced platelet aggregation by about 50%, but apoA1 Milano had no direct effect on vasoreactivity. This study provides further evidence for critical role of platelets in thrombosis. Use of apoA1 Milano offers a novel approach to inhibit arterial thrombosis.
Key Words: apoA1 • apolipoproteins • lipoproteins, HDL • thrombosis
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