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(Circulation Research. 2006;99:829.)
© 2006 American Heart Association, Inc.

Molecular Medicine

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

Robert DeKroon, Jennifer B. Robinette, Anita B. Hjelmeland, Emma Wiggins, Morven Blackwell, Mirta Mihovilovic, Makoto Fujii, John York, Janet Hart, Christopher Kontos, Jeremy Rich, Warren J. Strittmatter

From the Departments of Medicine (Neurology) (R.D., J.B.R., E.W., M.B., M.M., C.K., J.R., W.J.S.), Deane Laboratory; Surgery (A.B.H., J.R.); Pharmacology and Cancer Biology (J.Y., J.H., C.K.); and Neurobiology (J.R., W.J.S.), Duke University Medical Center, Durham, NC; and Laboratory of Molecular and Cellular Biochemistry (M.F.), Kyushu University, Fukuoka, Japan.

Correspondence to Robert DeKroon, Box 2900, Bryan Research Building, Department of Medicine (Neurology), Duke University Medical Center, Durham, NC 27710. E-mail dekro001{at}mc.duke.edu

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]P₃). We further demonstrate that APOE4-VLDL reduces PI(3,4,5)P₃, 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 increases the risk of atherosclerotic CVD.

Key Words: apolipoprotein E • SHIP2 • Akt • apoptosis • endothelial

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