Abstract
Background - Atherosclerosis has features of an inflammatory disease. Because cyclooxygenase (COX)-2 is expressed in atherosclerotic lesions and promotes inflammation, we tested the hypotheses that selective COX-2 inhibition would reduce early lesion formation in LDL receptor-deficient (LDLR-/-) mice and that macrophage COX-2 expression contributes to atherogenesis in LDLR-/- mice. Methods and Results - Treatment of male LDLR-/- mice fed the Western diet with rofecoxib or indomethacin for 6 weeks resulted in significant reductions in atherosclerosis in the proximal aorta (25% and 37%) and in the aorta en face (58% and 57%), respectively. Rofecoxib treatment did not inhibit platelet thromboxane production, a COX-1-mediated process, but it significantly reduced the urinary prostacyclin metabolite 2,3-dinor-6-keto-PGF1α. Fetal liver cell transplantation was used to generate LDLR-/- mice null for expression of the COX-2 gene by macrophages. After 8 weeks on the Western diet, COX-2-/-→LDLR-/- mice developed significantly less (33% to 39%) atherosclerosis than control COX-2+/+→LDLR-/- mice. In both the inhibitor studies and the transplant studies, serum lipids did not differ significantly between groups. Conclusions - The present studies provide strong pharmacological and genetic evidence that COX-2 promotes early atherosclerotic lesion formation in LDLR-/- mice in vivo. These results support the potential of anti-inflammatory approaches to the prevention of atherosclerosis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1816-1823 |
| Number of pages | 8 |
| Journal | Circulation |
| Volume | 105 |
| Issue number | 15 |
| DOIs | |
| State | Published - Apr 16 2002 |
| Externally published | Yes |
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Keywords
- Atherosclerosis
- Inflammation
- Macrophage
- Mice
- Transplantation
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
Cite this
Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. / Burleigh, Michael E.; Babaev, Vladimir R.; Oates, John A.; Harris, Raymond C.; Gautam, Shiva; Riendeau, Denis; Marnett, Lawrence J.; Morrow, Jason D.; Fazio, Sergio; Linton, MacRae F.
In: Circulation, Vol. 105, No. 15, 16.04.2002, p. 1816-1823.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice
AU - Burleigh, Michael E.
AU - Babaev, Vladimir R.
AU - Oates, John A.
AU - Harris, Raymond C.
AU - Gautam, Shiva
AU - Riendeau, Denis
AU - Marnett, Lawrence J.
AU - Morrow, Jason D.
AU - Fazio, Sergio
AU - Linton, MacRae F.
PY - 2002/4/16
Y1 - 2002/4/16
N2 - Background - Atherosclerosis has features of an inflammatory disease. Because cyclooxygenase (COX)-2 is expressed in atherosclerotic lesions and promotes inflammation, we tested the hypotheses that selective COX-2 inhibition would reduce early lesion formation in LDL receptor-deficient (LDLR-/-) mice and that macrophage COX-2 expression contributes to atherogenesis in LDLR-/- mice. Methods and Results - Treatment of male LDLR-/- mice fed the Western diet with rofecoxib or indomethacin for 6 weeks resulted in significant reductions in atherosclerosis in the proximal aorta (25% and 37%) and in the aorta en face (58% and 57%), respectively. Rofecoxib treatment did not inhibit platelet thromboxane production, a COX-1-mediated process, but it significantly reduced the urinary prostacyclin metabolite 2,3-dinor-6-keto-PGF1α. Fetal liver cell transplantation was used to generate LDLR-/- mice null for expression of the COX-2 gene by macrophages. After 8 weeks on the Western diet, COX-2-/-→LDLR-/- mice developed significantly less (33% to 39%) atherosclerosis than control COX-2+/+→LDLR-/- mice. In both the inhibitor studies and the transplant studies, serum lipids did not differ significantly between groups. Conclusions - The present studies provide strong pharmacological and genetic evidence that COX-2 promotes early atherosclerotic lesion formation in LDLR-/- mice in vivo. These results support the potential of anti-inflammatory approaches to the prevention of atherosclerosis.
AB - Background - Atherosclerosis has features of an inflammatory disease. Because cyclooxygenase (COX)-2 is expressed in atherosclerotic lesions and promotes inflammation, we tested the hypotheses that selective COX-2 inhibition would reduce early lesion formation in LDL receptor-deficient (LDLR-/-) mice and that macrophage COX-2 expression contributes to atherogenesis in LDLR-/- mice. Methods and Results - Treatment of male LDLR-/- mice fed the Western diet with rofecoxib or indomethacin for 6 weeks resulted in significant reductions in atherosclerosis in the proximal aorta (25% and 37%) and in the aorta en face (58% and 57%), respectively. Rofecoxib treatment did not inhibit platelet thromboxane production, a COX-1-mediated process, but it significantly reduced the urinary prostacyclin metabolite 2,3-dinor-6-keto-PGF1α. Fetal liver cell transplantation was used to generate LDLR-/- mice null for expression of the COX-2 gene by macrophages. After 8 weeks on the Western diet, COX-2-/-→LDLR-/- mice developed significantly less (33% to 39%) atherosclerosis than control COX-2+/+→LDLR-/- mice. In both the inhibitor studies and the transplant studies, serum lipids did not differ significantly between groups. Conclusions - The present studies provide strong pharmacological and genetic evidence that COX-2 promotes early atherosclerotic lesion formation in LDLR-/- mice in vivo. These results support the potential of anti-inflammatory approaches to the prevention of atherosclerosis.
KW - Atherosclerosis
KW - Inflammation
KW - Macrophage
KW - Mice
KW - Transplantation
UR - http://www.scopus.com/inward/record.url?scp=0037117652&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037117652&partnerID=8YFLogxK
U2 - 10.1161/01.CIR.0000014927.74465.7F
DO - 10.1161/01.CIR.0000014927.74465.7F
M3 - Article
C2 - 11956125
AN - SCOPUS:0037117652
VL - 105
SP - 1816
EP - 1823
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 15
ER -