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

Claudio Napoli, Carla Cicala, Francesco P. D'Armiento, Fiorentina Roviezzo, Pasquale Somma, Filomena De Nigris, Patrizia Zuliani, Mariarosaria Bucci, Lucia Aleotti, Alessandro Casini, Flavia Franconi, Giuseppe Cirino

Research output: Contribution to journalArticle

Abstract

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 111Indium-oxine 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.

Original languageEnglish
Pages (from-to)467-477
Number of pages11
JournalGeneral Pharmacology
Volume33
Issue number6
DOIs
Publication statusPublished - Dec 1999

Keywords

  • Antioxidants
  • Atherogenesis
  • LDL oxidation
  • Platelet
  • WHHL rabbit
  • Zofenopril

ASJC Scopus subject areas

  • Pharmacology

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  • Cite this

    Napoli, C., Cicala, C., D'Armiento, F. P., Roviezzo, F., Somma, P., De Nigris, F., Zuliani, P., Bucci, M., Aleotti, L., Casini, A., Franconi, F., & Cirino, G. (1999). Beneficial effects of ACE-inhibition with zofenopril on plaque formation and low-density lipoprotein oxidation in watanabe heritable hyperlipidemic rabbits. General Pharmacology, 33(6), 467-477. https://doi.org/10.1016/S0306-3623(99)00043-9