Apolipoprotein e4 allele is predictor of coronary artery disease death in elderly patients with type 2 diabetes mellitus

Gao, Xiang; You-ying, Liu; Zhi-song, Chen; He, Yusheng; Xiang-jiu, Yang

doi:10.1016/j.atherosclerosis.2004.02.015

Cited by 21 publications

(17 citation statements)

References 27 publications

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“…38 In addition, elderly patients with type 2 diabetes and the APOE4 allele have an increased risk of CVD death. 39 Therefore, the APOE4 allele may increase the risk of CVD by altering the progression of components of the metabolic syndrome. HDL binds the SR-BI scavenger receptor and mediates activation of the S1P 3 receptor, enhancing PI3K synthesis of PI(3,4,5)P 3 (PIP3) by the phosphorylation of PI(4,5)P 2 (PIP2) at the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

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APOE4 -VLDL Inhibits the HDL-Activated Phosphatidylinositol 3-Kinase/Akt Pathway via the Phosphoinositol Phosphatase SHIP2

DeKroon

Robinette

Hjelmeland

et al. 2006

Circulation Research

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Abstract-Endothelial cell dysfunction and apoptosis are critical in the pathogenesis of atherosclerotic cardiovascular disease (CVD). Both endothelial cell apoptosis and atherosclerosis are reduced by high-density lipoprotein (HDL). Low HDL levels increase the risk of CVD and are also a key characteristic of the metabolic syndrome. The apolipoprotein E4 (APOE4) allele also increases the risk of atherosclerosis and CVD. We previously demonstrated that the antiapoptotic activity of HDL is inhibited by APOE4 very-low-density lipoprotein (APOE4-VLDL) in endothelial cells, an effect similar to reducing the levels of HDL. Here we establish the intracellular mechanism by which APOE4-VLDL inhibits the antiapoptotic pathway activated by HDL. We show that APOE4-VLDL diminishes the phosphorylation of Akt by HDL but does not alter phosphorylation of c-Jun N-terminal kinase, p38, or Src family kinases by HDL. Furthermore APOE4-VLDL inhibits Akt phosphorylation by reducing the phosphatidylinositol 3-kinase product phosphatidylinositol-(3,4,5)-triphosphate (PI[3,4,5]P 3 ). We further demonstrate that APOE4-VLDL reduces PI(3,4,5)P 3 , through the phosphoinositol phosphatase SHIP2, and not through PTEN. SHIP2 is already implicated as an independent risk factor for type II diabetes, hypertension and obesity, which are also all components of the metabolic syndrome and independent risk factors for CVD. Significantly, the association between CVD and type 2 diabetes or hypertension is further increased by the APOE4 allele. Therefore the activation of SHIP2 by APOE4-VLDL, with the subsequent inhibition of the HDL/Akt pathway, is a novel and significant biological mechanism and may be a critical intermediate by which APOE4 Key Words: apolipoprotein E Ⅲ SHIP2 Ⅲ Akt Ⅲ apoptosis Ⅲ endothelial E ndothelial cell stress and dysfunction result in apoptotic cell death and are critical early events resulting in atherosclerotic cardiovascular disease (CVD). Endothelial cell apoptosis, proliferation, and differentiation are regulated by serum lipoproteins of four main classes: high-density (HDL), low-density (LDL), very-low-density (VLDL) lipoprotein and chylomicrons. Reduced HDL levels increase the risk of CVD and are observed in approximately half of all men with CVD. 1-3 HDL protects endothelial cells from apoptosis through its interaction with the scavenger receptor SR-BI (scavenger receptor class B type I) and the lysophospholipid receptor S1P 3 /EDG3 (sphingosine-1 phosphate subtype 3/endothelial differentiation gene 3). This HDL/receptor interaction results in the phosphorylation of Akt and the subsequent suppression of caspase-3/7 activity. 4 The apolipoprotein E4 (APOE4) allele also increases the risk of CVD. 5-11 ApoE has three common alleles, APOE2, -3, and -4, and mediates extracellular cholesterol and phospholipid transport by lipoprotein particles, regulating a variety of metabolic pathways. We previously demonstrated that total serum lipoproteins regulate endothelial cell apoptosis in an APOE genotype-specific manner. Lipoproteins...

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Section: Discussionmentioning

confidence: 99%

“…[37][38][39][40][41] In the Baltimore Longitudinal Study of Aging, the APOE4 allele was associated with elevated fasting plasma glucose levels in men. 37 Similarly, Elosua et al, found the APOE4 allele associated with higher fasting insulin and glucose levels in obese men, compared with obese men without the APOE4 allele.…”

Section: Discussionmentioning

confidence: 99%

APOE4 -VLDL Inhibits the HDL-Activated Phosphatidylinositol 3-Kinase/Akt Pathway via the Phosphoinositol Phosphatase SHIP2

DeKroon

Robinette

Hjelmeland

et al. 2006

Circulation Research

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“…The frequency of the ε4 allele is elevated among individuals with atherosclerosis (Menzel, Kladetzky et al 1983), Alzheimer's disease (AD) (Corder, Saunders et al 1993, Strittmatter, Saunders et al 1993), and with impaired cognitive function (Brayne, Harrington et al 1996). APOE is also associated with mortality (Lane, Gao et al 2003, Drenos and Kirkwood 2010, Beydoun, Beydoun et al 2013), coronary artery disease and death (Tiret, de Knijff et al 1994, Guang-da, You-ying et al 2004). …”

Section: Introductionmentioning

confidence: 99%

No association between Apoε4 alleles, HIV infection, age, neuropsychological outcome, or death

et al. 2014

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The ε4 allele of the ApoE gene may have important interactions with physical health and cognitive function among individuals with HIV disease. The purpose of this study is to examine the relationships between ε4, HIV disease, age, neuropsychological impairment and death in a large, well-characterized study sample. 2,846 men participating in the Multicenter AIDS Cohort Study had ApoE genotyping and neuropsychological test data available for analysis. We found a significant association between HIV infection and time to death (from any cause), as well as older age, race, and education. But, ApoE status was not significantly associated with time to death. Similarly, we found a significant association between HIV infection and time to incident cognitive impairment, as well as age, education, and HIV serostatus; Apoε4 status was not related to incident cognitive impairment. There were no significant interactions between ApoE, HIV infection, and age on cognitive impairment. These data replicate and strengthen prior findings of the lack of association between ApoE ε4 and cognitive outcomes in HIV disease. We conclude that within the specific constraints of an exclusively male study in which the majority of participants were less than 65 years of age (range: 22-87 years), it appears reasonable to conclude that the ε4 allele is not significantly interacting with HIV serostatus.

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“…Epidemiological studies have suggested that in certain populations, APOE genotype may influence plasma glucose and insulin levels (4,5), postprandial glucose response (6), the development of metabolic syndrome (7,8), and a myriad of diabetes complications (9). In addition, apoE4 carriers with diabetes have been shown to have increased carotid atherosclerosis (10), and elderly apoE4 carriers with diabetes have an increased risk of CVD-associated death (11). …”

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confidence: 99%

Apolipoprotein E4 Exaggerates Diabetic Dyslipidemia and Atherosclerosis in Mice Lacking the LDL Receptor

et al. 2011

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OBJECTIVEWe investigated the differential roles of apolipoprotein E (apoE) isoforms in modulating diabetic dyslipidemia—a potential cause of the increased cardiovascular disease risk of patients with diabetes.RESEARCH DESIGN AND METHODSDiabetes was induced using streptozotocin (STZ) in human apoE3 (E3) or human apoE4 (E4) mice deficient in the LDL receptor (LDLR−/−).RESULTSDiabetic E3LDLR−/− and E4LDLR−/− mice have indistinguishable levels of plasma glucose and insulin. Despite this, diabetes increased VLDL triglycerides and LDL cholesterol in E4LDLR−/− mice twice as much as in E3LDLR−/− mice. Diabetic E4LDLR−/− mice had similar lipoprotein fractional catabolic rates compared with diabetic E3LDLR−/− mice but had larger hepatic fat stores and increased VLDL secretion. Diabetic E4LDLR−/− mice demonstrated a decreased reliance on lipid as an energy source based on indirect calorimetry. Lower phosphorylated acetyl-CoA carboxylase content and higher gene expression of fatty acid synthase in the liver indicated reduced fatty acid oxidation and increased fatty acid synthesis. E4LDLR−/− primary hepatocytes cultured in high glucose accumulated more intracellular lipid than E3LDLR−/− hepatocytes concomitant with a 60% reduction in fatty acid oxidation. Finally, the exaggerated dyslipidemia in diabetic E4LDLR−/− mice was accompanied by a dramatic increase in atherosclerosis.CONCLUSIONSApoE4 causes severe dyslipidemia and atherosclerosis independent of its interaction with LDLR in a model of STZ-induced diabetes. ApoE4-expressing livers have reduced fatty acid oxidation, which contributes to the accumulation of tissue and plasma lipids.

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Apolipoprotein e4 allele is predictor of coronary artery disease death in elderly patients with type 2 diabetes mellitus

Cited by 21 publications

References 27 publications

APOE4 -VLDL Inhibits the HDL-Activated Phosphatidylinositol 3-Kinase/Akt Pathway via the Phosphoinositol Phosphatase SHIP2

APOE4 -VLDL Inhibits the HDL-Activated Phosphatidylinositol 3-Kinase/Akt Pathway via the Phosphoinositol Phosphatase SHIP2

No association between Apoε4 alleles, HIV infection, age, neuropsychological outcome, or death

Apolipoprotein E4 Exaggerates Diabetic Dyslipidemia and Atherosclerosis in Mice Lacking the LDL Receptor

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