Macrophage expression of peroxisome proliferator-activated receptor-α reduces atherosclerosis in low-density lipoprotein receptor-deficient mice

Vladimir R. Babaev, Hiroyuki Ishiguro, Lei Ding, Patricia G. Yancey, Dwayne E. Dove, William J. Kovacs, Clay F. Semenkovich, Sergio Fazio, MacRae F. Linton

Research output: Contribution to journalArticle

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Abstract

BACKGROUND - The peroxisome proliferator-activated receptor-α (PPARα) plays important roles in lipid metabolism, inflammation, and atherosclerosis. PPARα ligands have been shown to reduce cardiovascular events in high-risk subjects. PPARα expression by arterial cells, including macrophages, may exert local antiatherogenic effects independent of plasma lipid changes. METHODS AND RESULTS - To examine the contribution of PPARα expression by bone marrow-derived cells in atherosclerosis, male and female low-density lipoprotein receptor-deficient (LDLR) mice were reconstituted with bone marrow from PPARα or PPARα mice and challenged with a high-fat diet. Although serum lipids and lipoprotein profiles did not differ between the groups, the size of atherosclerotic lesions in the distal aorta of male and female PPARα→LDLR mice was significantly increased (44% and 46%, respectively) compared with controls. Male PPARα→LDLR mice also had larger (44%) atherosclerotic lesions in the proximal aorta than male PPARα→LDLR mice. Peritoneal macrophages from PPARα mice had increased uptake of oxidized LDL and decreased cholesterol efflux. PPARα macrophages had lower levels of scavenger receptor B type I and ABCA1 protein expression and an accelerated response of nuclear factor-κB-regulated inflammatory genes. A laser capture microdissection analysis verified suppressed scavenger receptor B type I and increased nuclear factor-κB gene expression levels in vivo in atherosclerotic lesions of PPARα→LDLR mice compared with the lesions of control PPARα→LDLR mice. CONCLUSIONS - These data demonstrate that PPARα expression by macrophages has antiatherogenic effects via modulation of cell cholesterol trafficking and inflammatory activity.

Original languageEnglish (US)
Pages (from-to)1404-1412
Number of pages9
JournalCirculation
Volume116
Issue number12
DOIs
StatePublished - Sep 1 2007

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Peroxisome Proliferator-Activated Receptors
LDL Receptors
Atherosclerosis
Macrophages
Scavenger Receptors
Aorta
ATP Binding Cassette Transporter 1
NFI Transcription Factors
Laser Capture Microdissection
Lipids
Peritoneal Macrophages
High Fat Diet
Lipid Metabolism
Bone Marrow Cells
LDL Cholesterol
Lipoproteins
Bone Marrow
Cholesterol
Ligands
Inflammation

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Babaev, Vladimir R. ; Ishiguro, Hiroyuki ; Ding, Lei ; Yancey, Patricia G. ; Dove, Dwayne E. ; Kovacs, William J. ; Semenkovich, Clay F. ; Fazio, Sergio ; Linton, MacRae F. / Macrophage expression of peroxisome proliferator-activated receptor-α reduces atherosclerosis in low-density lipoprotein receptor-deficient mice. In: Circulation. 2007 ; Vol. 116, No. 12. pp. 1404-1412.
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abstract = "BACKGROUND - The peroxisome proliferator-activated receptor-α (PPARα) plays important roles in lipid metabolism, inflammation, and atherosclerosis. PPARα ligands have been shown to reduce cardiovascular events in high-risk subjects. PPARα expression by arterial cells, including macrophages, may exert local antiatherogenic effects independent of plasma lipid changes. METHODS AND RESULTS - To examine the contribution of PPARα expression by bone marrow-derived cells in atherosclerosis, male and female low-density lipoprotein receptor-deficient (LDLR) mice were reconstituted with bone marrow from PPARα or PPARα mice and challenged with a high-fat diet. Although serum lipids and lipoprotein profiles did not differ between the groups, the size of atherosclerotic lesions in the distal aorta of male and female PPARα→LDLR mice was significantly increased (44{\%} and 46{\%}, respectively) compared with controls. Male PPARα→LDLR mice also had larger (44{\%}) atherosclerotic lesions in the proximal aorta than male PPARα→LDLR mice. Peritoneal macrophages from PPARα mice had increased uptake of oxidized LDL and decreased cholesterol efflux. PPARα macrophages had lower levels of scavenger receptor B type I and ABCA1 protein expression and an accelerated response of nuclear factor-κB-regulated inflammatory genes. A laser capture microdissection analysis verified suppressed scavenger receptor B type I and increased nuclear factor-κB gene expression levels in vivo in atherosclerotic lesions of PPARα→LDLR mice compared with the lesions of control PPARα→LDLR mice. CONCLUSIONS - These data demonstrate that PPARα expression by macrophages has antiatherogenic effects via modulation of cell cholesterol trafficking and inflammatory activity.",
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Macrophage expression of peroxisome proliferator-activated receptor-α reduces atherosclerosis in low-density lipoprotein receptor-deficient mice. / Babaev, Vladimir R.; Ishiguro, Hiroyuki; Ding, Lei; Yancey, Patricia G.; Dove, Dwayne E.; Kovacs, William J.; Semenkovich, Clay F.; Fazio, Sergio; Linton, MacRae F.

In: Circulation, Vol. 116, No. 12, 01.09.2007, p. 1404-1412.

Research output: Contribution to journalArticle

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T1 - Macrophage expression of peroxisome proliferator-activated receptor-α reduces atherosclerosis in low-density lipoprotein receptor-deficient mice

AU - Babaev, Vladimir R.

AU - Ishiguro, Hiroyuki

AU - Ding, Lei

AU - Yancey, Patricia G.

AU - Dove, Dwayne E.

AU - Kovacs, William J.

AU - Semenkovich, Clay F.

AU - Fazio, Sergio

AU - Linton, MacRae F.

PY - 2007/9/1

Y1 - 2007/9/1

N2 - BACKGROUND - The peroxisome proliferator-activated receptor-α (PPARα) plays important roles in lipid metabolism, inflammation, and atherosclerosis. PPARα ligands have been shown to reduce cardiovascular events in high-risk subjects. PPARα expression by arterial cells, including macrophages, may exert local antiatherogenic effects independent of plasma lipid changes. METHODS AND RESULTS - To examine the contribution of PPARα expression by bone marrow-derived cells in atherosclerosis, male and female low-density lipoprotein receptor-deficient (LDLR) mice were reconstituted with bone marrow from PPARα or PPARα mice and challenged with a high-fat diet. Although serum lipids and lipoprotein profiles did not differ between the groups, the size of atherosclerotic lesions in the distal aorta of male and female PPARα→LDLR mice was significantly increased (44% and 46%, respectively) compared with controls. Male PPARα→LDLR mice also had larger (44%) atherosclerotic lesions in the proximal aorta than male PPARα→LDLR mice. Peritoneal macrophages from PPARα mice had increased uptake of oxidized LDL and decreased cholesterol efflux. PPARα macrophages had lower levels of scavenger receptor B type I and ABCA1 protein expression and an accelerated response of nuclear factor-κB-regulated inflammatory genes. A laser capture microdissection analysis verified suppressed scavenger receptor B type I and increased nuclear factor-κB gene expression levels in vivo in atherosclerotic lesions of PPARα→LDLR mice compared with the lesions of control PPARα→LDLR mice. CONCLUSIONS - These data demonstrate that PPARα expression by macrophages has antiatherogenic effects via modulation of cell cholesterol trafficking and inflammatory activity.

AB - BACKGROUND - The peroxisome proliferator-activated receptor-α (PPARα) plays important roles in lipid metabolism, inflammation, and atherosclerosis. PPARα ligands have been shown to reduce cardiovascular events in high-risk subjects. PPARα expression by arterial cells, including macrophages, may exert local antiatherogenic effects independent of plasma lipid changes. METHODS AND RESULTS - To examine the contribution of PPARα expression by bone marrow-derived cells in atherosclerosis, male and female low-density lipoprotein receptor-deficient (LDLR) mice were reconstituted with bone marrow from PPARα or PPARα mice and challenged with a high-fat diet. Although serum lipids and lipoprotein profiles did not differ between the groups, the size of atherosclerotic lesions in the distal aorta of male and female PPARα→LDLR mice was significantly increased (44% and 46%, respectively) compared with controls. Male PPARα→LDLR mice also had larger (44%) atherosclerotic lesions in the proximal aorta than male PPARα→LDLR mice. Peritoneal macrophages from PPARα mice had increased uptake of oxidized LDL and decreased cholesterol efflux. PPARα macrophages had lower levels of scavenger receptor B type I and ABCA1 protein expression and an accelerated response of nuclear factor-κB-regulated inflammatory genes. A laser capture microdissection analysis verified suppressed scavenger receptor B type I and increased nuclear factor-κB gene expression levels in vivo in atherosclerotic lesions of PPARα→LDLR mice compared with the lesions of control PPARα→LDLR mice. CONCLUSIONS - These data demonstrate that PPARα expression by macrophages has antiatherogenic effects via modulation of cell cholesterol trafficking and inflammatory activity.

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