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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1213.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Cardiovascular Inflammation and Lesion Cell Apoptosis

A Novel Connection via the Interferon-Inducible Immunoproteasome

Zhaoqing Yang; Dmitry Gagarin; Georges St. Laurent, III; Neil Hammell; Ian Toma; Chien-an Hu; Ayaka Iwasa; Timothy A. McCaffrey

From the Department of Biochemistry and Molecular Biology, The Catharine Birch McCormick Genomics Center, & The Richard B. and Lynne V. Cheney Cardiovascular Institute (Z.Y., D.G., G.S.L., N.H., I.T., A.I., T.A.M.), George Washington University Medical Center, Washington, DC; Immunovirology – Biogenesis Group (G.S.L.), University of Antioquia, Colombia; and the Department of Biochemistry and Molecular Biology (C.H.), University of New Mexico School of Medicine, Albuquerque.

Correspondence to Tim McCaffrey, PhD, The George Washington Medical Center, Department of Biochemistry and Molecular Biology, 2300 I Street NW, Ross Hall 541, Washington, DC 20037. E-mail mcc{at}gwu.edu

Objective— Increasing evidence suggests that chronic inflammation contributes to atherogenesis, and that acute inflammatory events cause plaque rupture, thrombosis, and myocardial infarction. The present studies examined how inflammatory factors, such as interferon- (IFN), cause increased sensitivity to apoptosis in vascular lesion cells.

Methods and Results— Cells from the fibrous cap of human atherosclerotic lesions were sensitized by interferon- (IFN) to Fas-induced apoptosis, in a Bcl-X_L reversible manner. Microarray profiling identified 72 INF-induced transcripts with potential relevance to apoptosis. Half could be excluded because they were induced by IRF-1 overexpression, which did not sensitize to apoptosis. IFN treatment strongly reduced Mcl-1, phospho-Bcl-2 (ser70), and phospho-Bcl-X_L (ser62) protein levels. Candidate transcripts were modulated by siRNA, overexpression, or inhibitors to assess the effect on IFN-induced Fas sensitivity. Surprisingly, siRNA knockdown of PSMB8 (LMP7), an "immunoproteasome" component, reversed IFN-induced sensitivity to Fas ligation and prevented Fas/IFN-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-X_L. Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-X_L levels after IFN treatment.

Conclusions— Although critical for antigen presentation, the immunoproteasome appears to be a key link between inflammatory factors and the control of vascular cell apoptosis and may thus be an important factor in plaque rupture and myocardial infarction.

Cells from human atherosclerotic lesions are sensitized by IFN to Fas-induced apoptosis. Microarrays identified 72 IFN-induced transcripts relevant to apoptosis. siRNA knockdown of PSMB8 (LMP7), an "immunoproteasome" component, reversed IFN-induced sensitivity and prevented degradation of Mcl-1, a potent survival factor. The immunoproteasome may link inflammation to vascular cell apoptosis.

Key Words: apoptosis • inflammation • Mcl-1 • interferon- • LMP7 • PSMB8 • Fas • immunoproteasome

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