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J. Biol. Chem., Vol. 283, Issue 11, 6832-6842, March 14, 2008

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Interferon- Induces X-linked Inhibitor of Apoptosis-associated Factor-1 and Noxa Expression and Potentiates Human Vascular Smooth Muscle Cell Apoptosis by STAT3 Activation^*

Yalai Bai, Usman Ahmad, Yinong Wang, Jie H. Li, Jonathan C. Choy¹, Richard W. Kim², Nancy Kirkiles-Smith, Stephen E. Maher^¶, James G. Karras^||, C. Frank Bennett^||, Alfred L. M. Bothwell^¶, Jordan S. Pober^¶, and George Tellides³

From the Interdepartmental Program in Vascular Biology and Transplantation and the Departments of Surgery, Pathology, and ^¶Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510 and ^||ISIS Pharmaceuticals, Carlsbad, California 92008

Interferon (IFN)- actions on the vessel wall play an important role in the pathogenesis of arteriosclerosis, yet the contribution of different IFN- signaling pathways to the phenotypic modulation of vascular smooth muscle cells (VSMCs) are poorly understood. We investigated the effects of IFN- on VSMCs and arteries through interactions involving signal transducer and activator of transcription (STAT) proteins. In addition to STAT1 activation, IFN- consistently phosphorylated STAT3 in human VSMCs but weakly or not at all in human endothelial cells or mouse VSMCs. STAT3 activation resulted in nuclear translocation of this transcription factor. By selectively inhibiting STAT3 and not STAT1 signaling, we identified a number of candidate IFN--inducible, STAT3-dependent gene products by microarray analysis. Results for selected genes, including the pro-apoptotic molecules X-linked inhibitor of apoptosis associated factor-1 (XAF1) and Noxa, were verified by real time quantitative reverse transcription-PCR and immunoblot analyses. IFN--induced STAT3 and STAT1 signaling in VSMCs demonstrated reciprocal inhibition. STAT3 activation by IFN- sensitized VSMCs to apoptosis triggered by both death receptor- and mitochondrial-mediated pathways. Knock down of XAF1 and Noxa expression inhibited the priming of VSMCs to apoptotic stimuli by IFN-. Finally, we confirmed the in vivo relevance of our observations using a chimeric animal model of immunodeficient mice bearing human coronary artery grafts in which the expression of XAF1 and Noxa as well as the pro-apoptotic effects induced by IFN- were dependent on STAT3. The data suggest STAT1-independent signaling by IFN- via STAT3 that promotes the death of human VSMCs.

Received for publication, July 8, 2007 , and in revised form, December 11, 2007.

^* This work was supported in part by National Institutes of Health Grant PO1 HL70295. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.

¹ Recipient of a Canadian Institutes of Health Research Postdoctoral Fellowship.

² Recipient of a fellowship award from the Thoracic Surgery Foundation for Research and Education.

³ To whom correspondence should be addressed: Yale University School of Medicine, 295 Congress Ave., 454, New Haven, CT 06510. Tel.: 203-737-2298; Fax: 203-737-2293; E-mail: george.tellides{at}yale.edu.

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