Inhibition of early atherogenesis by losartan in monkeys with diet-induced hypercholesterolemia.
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 AT(1) blockade on fatty-streak formation, plasma lipids, and surrogate markers of vascular injury.


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 approximately 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 AT(1) 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.
Strawn
W B
WB
Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. bstrawn@wfubmc.edu
Chappell
M C
MC
Dean
R H
RH
Kivlighn
S
S
Ferrario
C M
CM
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001161:Arteriosclerosis / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D004032:Diet; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000209:etiology* / Q000276:immunology; D007107:Immune System / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D011897:Random Allocation; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2
D057911:Angiotensin Receptor Antagonists; D015415:Biomarkers; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D019808:Losartan