FoxO4 Regulates Tumor Necrosis Factor Alpha-Directed Smooth Muscle Cell Migration by Activating Matrix Metalloproteinase 9 Gene Transcription

Abstract

Phenotypic modulation of vascular smooth muscle cells (SMCs) in the blood vessel wall from a differentiated to a proliferative state during vascular injury and inflammation plays an important role in restenosis and atherosclerosis. Matrix metalloproteinase 9 (MMP9) is a member of the MMP family of proteases, which participate in extracellular matrix degradation and turnover. MMP9 is upregulated and required for SMC migration during the development of restenotic and atherosclerotic lesions. In this study, we show that FoxO4 activates transcription of the MMP9 gene in response to tumor necrosis factor alpha (TNF-α) signaling. Inhibition of FoxO4 expression by small interfering RNA or gene knockout reduces the abilities of SMCs to migrate in vitro and inhibit neointimal formation and MMP9 expression in vivo. We further show that both the N-terminal, Sp1-interactive domain and the C-terminal transactivation domain of FoxO4 are required for FoxO4-activated MMP9 transcription. TNF-α signaling upregulates nuclear FoxO4. Our studies place FoxO4 in the center of a transcriptional regulatory network that links gene transcription required for SMC remodeling to upstream cytokine signals and implicate FoxO4 as a potential therapeutic target for combating proliferative arterial diseases.

This study was supported by a scientist development grant from the American Heart Association and NIH RO1 HL085749-01 to Z.-P.L. and grants from the NIH and the Donald W. Reynolds Clinical Cardiovascular Research Center to E.N.O. R.A.D. is an American Cancer Society Research Professor and an Ellison Medical Foundation Scholar and is supported by the Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science and the NIH (grants PO1 CA095616 and MMHCC U01).

We thank G. Owens and T. Kitamura for reagents, H. Yanagisawa for fruitful discussions, and S. Hacker and J. Shelton for technical assistance.