Inhibition of cyclooxygenase with indomethacin phenethylamide reduces atherosclerosis in apoE-null mice.

Burleigh ME, Babaev VR, Patel MB, Crews BC, Remmel RP, Morrow JD, Oates JA, Marnett LJ, Fazio S, Linton MF
Biochem Pharmacol. 2005 70 (3): 334-42

PMID: 15950196 · DOI:10.1016/j.bcp.2005.04.044

Non-selective inhibition of cyclooxygenase (COX) has been reported to reduce atherosclerosis in both rabbit and murine models. In contrast, selective inhibition of COX-2 has been shown to suppress early atherosclerosis in LDL-receptor null mice but not more advanced lesions in apoE deficient (apoE(-/-)) mice. We investigated the efficacy of the novel COX inhibitor indomethacin phenethylamide (INDO-PA) on the development of different stages of atherosclerotic lesion formation in female apoE(-/-) mice. INDO-PA, which is highly selective for COX-2 in vitro, reduced platelet thromboxane production by 61% in vivo, indicating partial inhibition of COX-1 in vivo. Treatment of female apoE(-/-) mice with 5mg/kg INDO-PA significantly reduced early to intermediate aortic atherosclerotic lesion formation (44 and 53%, respectively) in both the aortic sinus and aorta en face compared to controls. Interestingly, there was no difference in the extent of atherosclerosis in the proximal aorta in apoE(-/-) mice treated from 11 to 21 weeks of age with INDO-PA, yet there was a striking (76%) reduction in lesion size by en face analysis in these mice. These studies demonstrate the ability of non-selective COX inhibition with INDO-PA to reduce early to intermediate atherosclerotic lesion formation in apoE(-/-) mice, supporting a role for anti-inflammatory approaches in the prevention of atherosclerosis.

MeSH Terms (13)

Animals Apolipoproteins E Arteriosclerosis Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Cyclooxygenase Inhibitors Female Indomethacin Mice Mice, Inbred C57BL Mice, Knockout Prostaglandin-Endoperoxide Synthases Thromboxanes

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