TY - JOUR
T1 - Apolipoprotein E receptor-2 deficiency enhances macrophage susceptibility to lipid accumulation and cell death to augment atherosclerotic plaque progression and necrosis
AU - Waltmann, Meaghan D.
AU - Basford, Joshua E.
AU - Konaniah, Eddy S.
AU - Weintraub, Neal L.
AU - Hui, David Y.
N1 - Funding Information:
This study was supported by the U.S. National Institutes of Health grants DK74932 and HL118001 (to D.Y.H.). M.D.W. was a pre-doctoral fellow in the U.S. National Institutes of Health training grant T32 HL007382 .
PY - 2014/9
Y1 - 2014/9
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Atherosclerosis
KW - Lipoprotein receptor
KW - P53
KW - PPARγ
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U2 - 10.1016/j.bbadis.2014.05.009
DO - 10.1016/j.bbadis.2014.05.009
M3 - Article
C2 - 24840660
AN - SCOPUS:84903459303
SN - 0925-4439
VL - 1842
SP - 1395
EP - 1405
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 9
ER -