Inhibition of arterial thrombus formation by ApoA1 Milano.
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.
Li
D
D
Department of Medicine, University of Florida College of Medicine, the VA Medical Center, Gainesville, Florida32610, USA.
Weng
S
S
Yang
B
B
Zander
D S
DS
Saldeen
T
T
Nichols
W W
WW
Khan
S
S
Mehta
J L
JL
D000818:Animals; D001012:Aorta, Abdominal; D001018:Aortic Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D016632:Apolipoprotein A-I / Q000097:blood / Q000494:pharmacology*; D002712:Chlorides; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D005290:Ferric Compounds; D006801:Humans; D008855:Microscopy, Electron, Scanning; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D013927:Thrombosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors