Abstract
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 5 mg/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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 334-342 |
| Number of pages | 9 |
| Journal | Biochemical Pharmacology |
| Volume | 70 |
| Issue number | 3 |
| DOIs | |
| State | Published - Aug 1 2005 |
Fingerprint
Keywords
- Aorta
- ApoE mice
- Atherosclerosis
- COX inhibition
- Cyclooxygenase
- Prostaglandins
Cite this
Inhibition of cyclooxygenase with indomethacin phenethylamide reduces atherosclerosis in apoE-null mice. / Burleigh, Michael E.; Babaev, Vladimir R.; Patel, Mayur B.; Crews, Brenda C.; Remmel, Rory P; Morrow, Jason D.; Oates, John A.; Marnett, Lawrence J.; Fazio, Sergio; Linton, MacRae F.
In: Biochemical Pharmacology, Vol. 70, No. 3, 01.08.2005, p. 334-342.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inhibition of cyclooxygenase with indomethacin phenethylamide reduces atherosclerosis in apoE-null mice
AU - Burleigh, Michael E.
AU - Babaev, Vladimir R.
AU - Patel, Mayur B.
AU - Crews, Brenda C.
AU - Remmel, Rory P
AU - Morrow, Jason D.
AU - Oates, John A.
AU - Marnett, Lawrence J.
AU - Fazio, Sergio
AU - Linton, MacRae F.
PY - 2005/8/1
Y1 - 2005/8/1
N2 - 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 5 mg/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.
AB - 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 5 mg/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.
KW - Aorta
KW - ApoE mice
KW - Atherosclerosis
KW - COX inhibition
KW - Cyclooxygenase
KW - Prostaglandins
UR - http://www.scopus.com/inward/record.url?scp=21344447800&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=21344447800&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2005.04.044
DO - 10.1016/j.bcp.2005.04.044
M3 - Article
C2 - 15950196
AN - SCOPUS:21344447800
VL - 70
SP - 334
EP - 342
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 3
ER -