(Circulation. 2000;101:1586.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Inhibition of Early Atherogenesis by Losartan in Monkeys With Diet-Induced Hypercholesterolemia
From Wake Forest University School of Medicine, Winston-Salem, NC (W.B.S., M.C.C., R.H.D., C.M.F.), and Merck & Co, West Point, Pa (S.K.).
Correspondence to William B. Strawn, DVM, PhD, Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157. E-mail bstrawn{at}wfubmc.edu
Background—Angiotensin II may contribute to atherogenesis by facilitating the proliferative and inflammatory response to hypercholesterolemia. This study determined, in a primate model of diet-induced atherosclerosis, the effect of AT1 blockade on fatty-streak formation, plasma lipids, and surrogate markers of vascular injury.
Methods and Results—Male cynomolgus monkeys fed a diet containing
0.067 mg cholesterol/kJ for 20 weeks were given
losartan (180 mg/d, n=6) or vehicle (n=8) for 6 weeks starting
at week 12 of the dietary regimen. Arterial pressure, heart
rate, plasma total and lipoprotein cholesterol
concentrations, and lipoprotein particle sizes and subclass
distributions were unaffected by treatment. Losartan caused
significant (P<0.05) increases in plasma
angiotensin II and angiotensin-(1–7). Compared
with vehicle-treated controls, losartan reduced the extent of
fatty streak in the aorta, the coronary arteries, and the
carotid arteries by 
50% (P<0.05). A significant
(P<0.05) reduction in the susceptibility of LDL to in
vitro oxidation, serum levels of monocyte chemoattractant protein-1,
and circulating monocyte CD11b expression were also associated with
losartan treatment. In addition, serum levels of vascular cell
adhesion molecule-1 and E-selectin did not change during treatment but
increased after discontinuation of losartan. Serum C-reactive
protein, platelet aggregability, and white cell counts were not
modified by losartan.
Conclusions—This study demonstrates for the first time an antiatherogenic effect of AT1 receptor blockade in nonhuman primates. Losartan inhibited fatty-streak formation through mechanisms that may include protection of LDL from oxidation and suppression of vascular monocyte activation and recruitment factors.
Key Words: atherosclerosis • angiotensin • cell adhesion molecules • hypercholesterolemia • lipoproteins
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