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

Vladimir R. Babaev, Lei Ding, Jeff Reese, Jason D. Morrow, Matthew D. Breyer, Sudhansu K. Dey, Sergio Fazio, MacRae F. Linton

Research output: Contribution to journalArticle

25 Citations (Scopus)

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→LDLRmice compared with COX-1→LDLRmice, whereas the extent of atherosclerosis was unchanged in COX-1/COX- 2→LDLRmice. 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.

Original languageEnglish (US)
Pages (from-to)108-117
Number of pages10
JournalCirculation
Volume113
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

Fingerprint

Cyclooxygenase 1
LDL Receptors
Apolipoproteins E
Bone Marrow Cells
Atherosclerosis
Bone Marrow
Thromboxanes
Blood Platelets
Macrophages
Low Density Lipoprotein Receptor-Related Protein-1
Cell Transplantation
Peritoneal Macrophages
Liver Transplantation
Lipoproteins
Lipopolysaccharides

Keywords

  • Cyclooxygenase
  • Macrophages
  • Platelets
  • Prostaglandins
  • Thromboxane

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Cyclooxygenase-1 deficiency in bone marrow cells increases early atherosclerosis in apolipoprotein E- and low-density lipoprotein receptor-null mice. / Babaev, Vladimir R.; Ding, Lei; Reese, Jeff; Morrow, Jason D.; Breyer, Matthew D.; Dey, Sudhansu K.; Fazio, Sergio; Linton, MacRae F.

In: Circulation, Vol. 113, No. 1, 01.2006, p. 108-117.

Research output: Contribution to journalArticle

Babaev, Vladimir R. ; Ding, Lei ; Reese, Jeff ; Morrow, Jason D. ; Breyer, Matthew D. ; Dey, Sudhansu K. ; Fazio, Sergio ; Linton, MacRae F. / Cyclooxygenase-1 deficiency in bone marrow cells increases early atherosclerosis in apolipoprotein E- and low-density lipoprotein receptor-null mice. In: Circulation. 2006 ; Vol. 113, No. 1. pp. 108-117.
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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→LDLRmice compared with COX-1→LDLRmice, whereas the extent of atherosclerosis was unchanged in COX-1/COX- 2→LDLRmice. 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.",
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T1 - Cyclooxygenase-1 deficiency in bone marrow cells increases early atherosclerosis in apolipoprotein E- and low-density lipoprotein receptor-null mice

AU - Babaev, Vladimir R.

AU - Ding, Lei

AU - Reese, Jeff

AU - Morrow, Jason D.

AU - Breyer, Matthew D.

AU - Dey, Sudhansu K.

AU - Fazio, Sergio

AU - Linton, MacRae F.

PY - 2006/1

Y1 - 2006/1

N2 - 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→LDLRmice compared with COX-1→LDLRmice, whereas the extent of atherosclerosis was unchanged in COX-1/COX- 2→LDLRmice. 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.

AB - 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→LDLRmice compared with COX-1→LDLRmice, whereas the extent of atherosclerosis was unchanged in COX-1/COX- 2→LDLRmice. 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.

KW - Cyclooxygenase

KW - Macrophages

KW - Platelets

KW - Prostaglandins

KW - Thromboxane

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