Inhibition of arterial thrombus formation by apoA1 Milano

The mutant form of human apoA1, known as apoA1 Milano, is formed as a resul t of arginine 173 to cysteine substitution and inhibits experimental athero sclerosis in cholesterol-fed animals. This study was designed to determine if apoA1 Milano would modify arterial thrombogenesis. Sprague Dawley rats w ere intravenously administered the carrier alone (n = 8) or apoA1 Milano (2 0 mg.kg(-1).d(-1) for 4 to 10 days, n = 17). The abdominal cavity was opene d, and the abdominal aorta was isolated. Whatman paper impregnated with 35% FeCl3 was wrapped around the surface of the aorta, and aortic flow was rec orded continuously. In carrier-treated rats, an occlusive platelet-fibrin-r ich thrombus was formed in 21.2 +/- 4.1 (meant SD) minutes. Treatment of ra ts 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 thrombu s (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 Milan o levels were elevated in apoA1 Milano-treated rats. In in vitro studies, i ncubation of platelets with apoA1 Milano reduced ADP-induced platelet aggre gation by about 50%, but apoA1 Milano had no direct effect on vasoreactivit y. This study provides further evidence for critical role of platelets in t hrombosis. Use of apoA1 Milano offers a novel approach to inhibit arterial thrombosis.