Inhibition of cyclooxygenase with indomethacin phenethylamide reduces atherosclerosis in apoE-null mice.
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.
Burleigh
Michael E
ME
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6300, USA.
Babaev
Vladimir R
VR
Patel
Mayur B
MB
Crews
Brenda C
BC
Remmel
Rory P
RP
Morrow
Jason D
JD
Oates
John A
JA
Marnett
Lawrence J
LJ
Fazio
Sergio
S
Linton
Macrae F
MF
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013931:Thromboxanes / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D001057:Apolipoproteins E; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D013931:Thromboxanes; C489645:indomethacin phenethylamide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin