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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1610.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Apolipoprotein E Interrupts Interleukin-1ß Signaling in Vascular Smooth Muscle Cells

Akira Kawamura; Daniel Baitsch; Ralph Telgmann; Renata Feuerborn; Gabriele Weissen-Plenz; Claudia Hagedorn; Keijiro Saku; Stefan-Martin Brand-Herrmann; Arnold von Eckardstein; Gerd Assmann; Jerzy-Roch Nofer

From the Departments of Lipid Metabolism (A.K., D.B., R.F., G.A., J.-R.N.), Molecular Genetics of Cardiovascular Diseases (R.T., C.H., S.-M.B.-H.), and Molecular Cardiology (G.W.-P.), Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Germany; the Department of Cardiology (A.K., K.S.), Fukuoka University School of Medicine, Fukuoka, Japan; the Institut für Klinische Chemie (A.v.E.), Universitäts-Spital Zürich, Zürich, Switzerland; and the Institut für Klinische Chemie und Laboratoriumsmedizin (G.A., J.-R.N.), Westfälische Wilhelms-Universität, Münster, Germany.

Correspondence to Jerzy-Roch Nofer, MD, MBA, Institut für Klinische Chemie und Laboratoriumsmedizin, Universitätsklinikum Münster, Albert Schweizer Str. 33, 48129 Münster, Germany. E-mail nofer{at}uni-muenster.de

Objectives— Apolipoprotein E (apoE) exerts antiatherogenic effects but precise mechanisms remain unclear. We here investigated the effect of apoE on intracellular signaling by interleukin-1ß (IL-1ß), a proinflammatory cytokine present in atherosclerotic lesions.

Methods and Results— IL-1ß-induced expression and activation of inducible nitric oxide synthase and cyclooxygenase-2 were inhibited by apoE in vascular smooth muscle cells (VSMCs). These inhibitory effects were linked to the suppression of both NF-B and activating protein-1 (AP-1) transactivation, suggesting that the interruption of IL-1ß signaling occurs upstream of transcription factors. Studies in VSMCs overexpressing IL-1ß signaling intermediates revealed that NF-B transactivation was inhibited by apoE in MyD88- and IRAK1- but not in TRAF6-transfected cells. Furthermore, apoE prevented IRAK1 phosphorylation and IRAK1-TRAF6 but not MyD88-IRAK1 complex formation. Inhibitory effects of apoE on IL-1ß signaling were abolished after silencing LDL receptor-related protein-1 (LRP1) expression with siRNA. In addition, inhibitors of adenylyl cyclase and protein kinase A (PKA) restored IL-1ß signaling in apoE-treated VSMCs, whereas apoE stimulated PKA activity. ApoE inhibited VSMC activation in response to IL-18 but not to tumor necrosis factor- or polyinosinic:polycytidylic acid.

Conclusion— ApoE targets IRAK-1 activation and thereby interrupts IL-1ß and IL-18 signaling in VSMCs. This antiinflammatory effect represents a novel antiatherogenic activity of apoE.

Apolipoprotein E (apoE) exerts antiatherogenic effects, but precise mechanisms remain unclear. The present study demonstrates that apoE suppress IL-1ß-induced inflammatory activation of vascular smooth muscle cells by targeting IL receptor-associated kinase-1 (IRAK-1) and transcription factors NF-B and AP-1 in a process dependent on protein kinase A (PKA).

Key Words: apolipoprotein E • IL-1ß • vascular smooth muscle cells • inflammation • atherosclerosis

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