Antiatherosclerotic properties of EP2302, a novel squalene synthase inhibitor, in the cholesterol-fed rabbit.
EP2302 is a novel nitric oxide donor compound that inhibits squalene synthase. We hypothesized that EP2302 can reduce atherosclerosis in the cholesterol-fed rabbit atherosclerosis model. Animals were fed a high-cholesterol (HC) diet for 4 weeks. Animals subsequently received drug or placebo for 4 (n = 15) or 12 weeks (n = 15) while on HC diet. A third group (n = 16) received drug or placebo for 4 weeks while on regular diet (regression group). No significant differences were observed in circulating lipids among any of the treatment groups at each time point during HC intake. The perimeter and area of the ascending aorta covered by lesions were significantly decreased in animals treated with 2 mg/kg EP2302 for 4 weeks (44% and 42% reduction, respectively). Moreover, a significant decrease in the perimeter of the ascending and descending aorta covered by lesions was observed in animals treated with 2 mg/kg EP2302 for 12 weeks (73% and 44% reduction, respectively) as well as in the regression group (61% and 65% reduction, respectively). Treatment with EP2302 did not cause any toxicity in animal vital organs. We have shown that EP2302 inhibits atherosclerosis in the cholesterol-fed rabbit and therefore may serve as a candidate drug to be tested in humans for atherosclerosis-related disorders.
Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.
Anna
A
Tavridou
Loukas
L
Kaklamanis
Apostolos
A
Papalois
Angeliki P
AP
Kourounakis
Eleni A
EA
Rekka
Panos N
PN
Kourounakis
Avgui
A
Charalambous
Vangelis G
VG
Manolopoulos
D000818:Animals; D000975:Antioxidants / Q000009:adverse effects / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000503:physiopathology; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000494:pharmacology*; D002784:Cholesterol / Q000009:adverse effects*; D003324:Coronary Artery Disease / Q000517:prevention & control*; D004032:Diet; D004195:Disease Models, Animal; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D008055:Lipids / Q000097:blood; D009025:Morpholines / Q000009:adverse effects / Q000494:pharmacology*; D011817:Rabbits
D000975:Antioxidants; D001713:Biphenyl Compounds; C500325:EP2302; D008055:Lipids; D009025:Morpholines; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase