FoxO4 regulates tumor necrosis factor alpha-directed smooth muscle cell migration by activating matrix metalloproteinase 9 gene transcription.
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-alpha) 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-alpha 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.
Li
Hao
H
Department of Internal Medicine, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9148, USA.
Liang
Jianping
J
Castrillon
Diego H
DH
DePinho
Ronald A
RA
Olson
Eric N
EN
Liu
Zhi-Ping
ZP
D000818:Animals; D017209:Apoptosis; D002339:Carotid Arteries / Q000166:cytology / Q000378:metabolism; D016893:Carotid Stenosis / Q000201:enzymology / Q000473:pathology; D002465:Cell Movement; D002478:Cells, Cultured; D004789:Enzyme Activation; D004790:Enzyme Induction; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D051381:Rats; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D017539:Tunica Intima / Q000473:pathology
D051858:Forkhead Transcription Factors; D016329:Sp1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9