Cyclooxygenase-1 deficiency in bone marrow cells increases early atherosclerosis in apolipoprotein E- and low-density lipoprotein receptor-null mice.

Abstract

BACKGROUND:

Cyclooxygenase-1 (COX-1) has been implicated in the pathogenesis of atherothrombosis and is expressed by the major cell types of atherosclerotic lesions. COX-1-mediated platelet thromboxane (TX) production has been proposed to promote both early atherosclerosis and thrombosis. Here, we examined the impact of COX-1 deficiency in bone marrow-derived cells on early atherogenesis in the mouse.

METHODS AND RESULTS:

LDL receptor (LDLR)(-/-) and apolipoprotein E (apoE)(-/-) recipient mice were lethally irradiated and transplanted with COX-1(-/-) bone marrow. Mice reconstituted with COX-1(-/-) marrow had nearly complete (99.7%) loss of platelet TXA2 and significantly suppressed levels of macrophage and urinary TXA2 metabolites. Serum lipid levels and lipoprotein distributions did not differ between recipients reconstituted with COX-1(+/+) and COX-1(-/-) marrow. Surprisingly, the extent of atherosclerotic lesions in both LDLR(-/-) and apoE(-/-) mice reconstituted with COX-1(-/-) marrow was increased significantly compared with control mice transplanted with COX-1(+/+) marrow. Peritoneal macrophages isolated from LDLR(-/-) mice reconstituted with COX-1(-/-) marrow had increased lipopolysaccharide-induced levels of COX-2 mRNA and protein expression. Fetal liver cell transplantation studies revealed a 30% increase in atherosclerosis in COX-1(-/-)-->LDLR(-/-)mice compared with COX-1(+/+)-->LDLR(-/-)mice, whereas the extent of atherosclerosis was unchanged in COX-1(-/-)/COX-2(-/-)-->LDLR(-/-)mice.

CONCLUSIONS:

COX-1 deficiency in bone marrow-derived cells worsens early atherosclerosis in apoE(-/-) and LDLR(-/-) mice despite virtual elimination of platelet TX production. These data demonstrate that platelet TX production does not aggravate early atherosclerotic lesion formation and that upregulation of COX-2 expression in COX-1(-/-) macrophages is proatherogenic.

• Authors: Vladimir R Babaev, Lei Ding, Jeff Reese, Jason D Morrow, Matthew D Breyer, Sudhansu K Dey, Sergio Fazio, MacRae F Linton
• Journal: Circulation (Circulation) Vol. 113 Issue 1 Pg. 108-17 (Jan 03 2006) ISSN: 1524-4539 [Electronic] United States
• PMID: 16380543 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Receptors, LDL
• Thromboxane A2
• Cyclooxygenase 1

Topics

• Animals
• Apolipoproteins E (deficiency)
• Atherosclerosis (etiology)
• Bone Marrow Cells (enzymology)
• Bone Marrow Transplantation
• Cyclooxygenase 1 (deficiency, genetics)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Receptors, LDL (deficiency)
• Thromboxane A2 (biosynthesis, physiology)
• Up-Regulation