Bisphosphonates induce inflammation and rupture of atherosclerotic plaques in apolipoprotein-E null mice.
The apolipoprotein E knockout (Apo-E-/-) mouse is a well-known model of atherosclerosis. Bisphosphonates, through their affinity to hydroxyapatite, are known to reduce arterial calcification in several animal models. Thus, we examined the effect of two therapeutically used oral bisphosphonates, alendronate and risedronate, on plaque formation in the Apo-E-/- mouse. The drugs were administered by gavage to 16-week-old Apo-E-/- mice for 8 weeks. At 8 weeks, there was no difference in bone mineral density (BMD) of the alendronate- and risedronate-treated mice at any site. A time-dependent increase in BMD was demonstrated in Apo-E-/- mice with risedronate (p<0.01). Histological evaluation revealed that both bisphosphonates caused atherosclerotic plaque rupture. Five of 17 mice had severe inflammation with or without plaque rupture, while seven mice showed inflammation, but without plaque rupture. Neither caspase 3 nor metalloproteinases 2 and 9 were increased in ruptured plaques on immunocytochemistry. Quantitative measurements of arterial caliber remained unaffected. Our finding of plaque inflammation and rupture in bisphosphonate-treated Apo-E-/- mice may provide the first animal model for studies aimed at characterizing mechanisms of plaque rupture in animal models.
Shimshi
Mona
M
Department of Medicine, The Mount Sinai Bone Program, The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY 07936-1080, USA. mona.shimshi@pharma.novartis.com
Abe
Etsuko
E
Fisher
Edward A
EA
Zaidi
Mone
M
Fallon
John T
JT
D019386:Alendronate / Q000008:administration & dosage*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D016893:Carotid Stenosis / Q000188:drug therapy / Q000209:etiology / Q000276:immunology / Q000473:pathology; D004164:Diphosphonates / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D012968:Etidronic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000068296:Risedronic Acid; D016896:Treatment Outcome
D001057:Apolipoproteins E; D004164:Diphosphonates; D000068296:Risedronic Acid; D012968:Etidronic Acid; D019386:Alendronate