Apolipoprotein E receptor-2 deficiency enhances macrophage susceptibility to lipid accumulation and cell death to augment atherosclerotic plaque progression and necrosis

Meaghan D. Waltmann, Joshua E. Basford, Eddy S. Konaniah, Neal Lee Weintraub, David Y. Hui

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Genome-wide association studies have linked LRP8 polymorphisms to premature coronary artery disease and myocardial infarction in humans. However, the mechanisms by which dysfunctions of apolipoprotein E receptor-2 (apoER2), the protein encoded by LRP8 gene, influence atherosclerosis have not been elucidated completely. The current study focused on the role of apoER2 in macrophages, a cell type that plays an important role in atherosclerosis. Results showed that apoER2-deficient mouse macrophages accumulated more lipids and were more susceptible to oxidized LDL (oxLDL)-induced death compared to control cells. Consistent with these findings, apoER2 deficient macrophages also displayed defective serum-induced Akt activation and higher levels of the pro-apoptotic protein phosphorylated p53. Furthermore, the expression and activation of peroxisome proliferator-activated receptor γ (PPARγ) were increased in apoER2-deficient macrophages. Deficiency of apoER2 in hypercholesterolemic LDL receptor-null mice (Lrp8-/-Ldlr-/- mice) also resulted in accelerated atherosclerosis with more complex lesions and extensive lesion necrosis compared to Lrp8+/+Ldlr-/- mice. The atherosclerotic plaques of Lrp8-/-Ldlr-/- mice displayed significantly higher levels of p53-positive macrophages, indicating that the apoER2-deficient macrophages contribute to the accelerated atherosclerotic lesion necrosis observed in these animals. Taken together, this study indicates that apoER2 in macrophages limits PPARγ expression and protects against oxLDL-induced cell death. Thus, abnormal apoER2 functions in macrophages may at least in part contribute to the premature coronary artery disease and myocardial infarction in humans with LRP8 polymorphisms. Moreover, the elevated PPARγ expression in apoER2-deficient macrophages suggests that LRP8 polymorphism may be a genetic modifier of cardiovascular risk with PPARγ therapy.

Original languageEnglish (US)
Pages (from-to)1395-1405
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1842
Issue number9
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Atherosclerotic Plaques
Cell Death
Necrosis
Macrophages
Lipids
Peroxisome Proliferator-Activated Receptors
Atherosclerosis
Coronary Artery Disease
Myocardial Infarction
low density lipoprotein receptor-related protein 8
Apoptosis Regulatory Proteins
LDL Receptors
Genome-Wide Association Study

Keywords

  • Apoptosis
  • Atherosclerosis
  • Lipoprotein receptor
  • P53
  • PPARγ

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

Cite this

Apolipoprotein E receptor-2 deficiency enhances macrophage susceptibility to lipid accumulation and cell death to augment atherosclerotic plaque progression and necrosis. / Waltmann, Meaghan D.; Basford, Joshua E.; Konaniah, Eddy S.; Weintraub, Neal Lee; Hui, David Y.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1842, No. 9, 01.01.2014, p. 1395-1405.

Research output: Contribution to journalArticle

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abstract = "Genome-wide association studies have linked LRP8 polymorphisms to premature coronary artery disease and myocardial infarction in humans. However, the mechanisms by which dysfunctions of apolipoprotein E receptor-2 (apoER2), the protein encoded by LRP8 gene, influence atherosclerosis have not been elucidated completely. The current study focused on the role of apoER2 in macrophages, a cell type that plays an important role in atherosclerosis. Results showed that apoER2-deficient mouse macrophages accumulated more lipids and were more susceptible to oxidized LDL (oxLDL)-induced death compared to control cells. Consistent with these findings, apoER2 deficient macrophages also displayed defective serum-induced Akt activation and higher levels of the pro-apoptotic protein phosphorylated p53. Furthermore, the expression and activation of peroxisome proliferator-activated receptor γ (PPARγ) were increased in apoER2-deficient macrophages. Deficiency of apoER2 in hypercholesterolemic LDL receptor-null mice (Lrp8-/-Ldlr-/- mice) also resulted in accelerated atherosclerosis with more complex lesions and extensive lesion necrosis compared to Lrp8+/+Ldlr-/- mice. The atherosclerotic plaques of Lrp8-/-Ldlr-/- mice displayed significantly higher levels of p53-positive macrophages, indicating that the apoER2-deficient macrophages contribute to the accelerated atherosclerotic lesion necrosis observed in these animals. Taken together, this study indicates that apoER2 in macrophages limits PPARγ expression and protects against oxLDL-induced cell death. Thus, abnormal apoER2 functions in macrophages may at least in part contribute to the premature coronary artery disease and myocardial infarction in humans with LRP8 polymorphisms. Moreover, the elevated PPARγ expression in apoER2-deficient macrophages suggests that LRP8 polymorphism may be a genetic modifier of cardiovascular risk with PPARγ therapy.",
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AU - Weintraub, Neal Lee

AU - Hui, David Y.

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