Beneficial effects of ACE-inhibition with zofenopril on plaque formation and low-density lipoprotein oxidation in watanabe heritable hyperlipidemic rabbits

The effects of angiotensin-converting enzyme (ACE)-inhibition with zofenopr il on the development of atherosclerosis and low-density lipoprotein (LDL) oxidation were determined in Watanabe Heritable Hyperlipidemic (WHHL) rabbi ts. Rabbits received either placebo (n = 6) or 0.5 mg/kg/day of zofenopril (n = 6). After 6 weeks of treatment, the computer-assisted analysis reveale d that zofenopril reduced the aortic and common carotid corrected cumulativ e lesion area by 34% and 39%, respectively (p < 0.05 vs placebo-treated gro up). The intimal/medial ratio of the largest fatty streaks was 0.426 +/- 0. 158 in the zofenopril-treated group and 0.875 +/- 0.238 in the placebo-trea ted group (p < 0.05). Furthermore, we found in the zofenopril-treated group smaller lesions with an intimal/medial ratio of zofenopril also reduced pl asmatic LDL oxidation, as shown by significant reduction of malondialdehyde content (p < 0.01) and relative agarose gel mobility (p < 0.05), as well a s by the prolongation of the lag-time (p < 0.05), Compared to zofenopril-tr eated rabbits, arterial sections of the placebo-group had significant incre ase in the intimal presence of macrophages-derived foam cells (p < 0.05), o x-LDL (p < 0.01), and native LDL (p < 0.01) detected by immunocytochemistry with RAM-11, MDA2 and NP1533975 monoclonal antibodies, respectively. To in vestigate the amount of platelet accumulation in the atherosclerotic plaque we also measured platelet-associated radioactivity. Autologous platelets w ere labeled with (111)Indium-oxine and injected intravenously. After 2 hour s, WHHL were sacrificed and arterial sections were counted for platelet-ass ociated radioactivity. In the placebo-treated group, platelet radioactivity was 0.52 +/- 0.12 equivalent of radioactivity per mg of tissue in the comm on carotid and 0.25 +/- 0.18 in the abdominal aorta; in contrast, rabbits t reated by zofenopril had 0.20 +/- 0.12 in the com mon carotid and 0.06 +/- 0.01 in the abdominal aorta. These data indicate that ACE-inhibition with z ofenopril has antiatherosclerotic and antioxidant effects in WKHL-rabbits. Our results also shows that these effects could be linked to a reduced wall -associated platelet deposition at the site of atherosclerotic lesions. (C) 2000 Elsevier Science Inc. All rights reserved.