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 zofenopril on the development of atherosclerosis and low-density lipoprotein (LDL) oxidation were determined in Watanabe Heritable Hyperlipidemic (WHHL) rabbits. 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 revealed that zofenopril reduced the aortic and common carotid corrected cumulative lesion area by 34% and 39%, respectively (p < 0.05 vs placebo-treated group). 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-treated group (p < 0.05). Furthermore, we found in the zofenopril-treated group smaller lesions with an intimal/medial ratio of zofenopril also reduced plasmatic LDL oxidation, as shown by significant reduction of malondialdehyde content (p < 0.01) and relative agarose gel mobility (p < 0.05), as well as by the prolongation of the lag-time (p < 0.05). Compared to zofenopril-treated rabbits, arterial sections of the placebo-group had significant increase in the intimal presence of macrophages-derived foam cells (p < 0.05), ox-LDL (p < 0.01), and native LDL (p < 0.01) detected by immunocytochemistry with RAM-11, MDA2 and NP1533975 monoclonal antibodies, respectively. To investigate the amount of platelet accumulation in the atherosclerotic plaque we also measured platelet-associated radioactivity. Autologous platelets were labeled with 111Indiumoxine and injected intravenously. After 2 hours, WHHL were sacrificed and arterial sections were counted for platelet-associated radioactivity. In the placebo-treated group, platelet radioactivity was 0.52+/-0.12 equivalent of radioactivity per mg of tissue in the common carotid and 0.25+/-0.18 in the abdominal aorta; in contrast, rabbits treated by zofenopril had 0.20+/-0.12 in the common carotid and 0.06+/-0.01 in the abdominal aorta. These data indicate that ACE-inhibition with zofenopril has antiatherosclerotic and antioxidant effects in WHHL-rabbits. Our results also shows that these effects could be linked to a reduced wall-associated platelet deposition at the site of atherosclerotic lesions.
Napoli
C
C
Department of Clinical and Experimental Medicine, Federico II University of Naples, Italy.
Cicala
C
C
D'Armiento
F P
FP
Roviezzo
F
F
Somma
P
P
de Nigris
F
F
Zuliani
P
P
Bucci
M
M
Aleotti
L
L
Casini
A
A
Franconi
F
F
Cirino
G
G
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001161:Arteriosclerosis / Q000517:prevention & control*; D001792:Blood Platelets / Q000378:metabolism; D002216:Captopril / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D011817:Rabbits
D000806:Angiotensin-Converting Enzyme Inhibitors; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; C044958:zofenopril; D002216:Captopril