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J. Biol. Chem., Vol. 281, Issue 52, 40429-40439, December 29, 2006

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Down-regulation of Manganese-Superoxide Dismutase through Phosphorylation of FOXO3a by Akt in Explanted Vascular Smooth Muscle Cells from Old Rats^*

Muyao Li, Jen-Fu Chiu¹, Brooke T. Mossman^¶, and Naomi K. Fukagawa²

From the Departments of Medicine, ^¶Pathology, and Biochemistry, University of Vermont College of Medicine, Burlington, Vermont 05405

Manganese-superoxide dismutase (MnSOD) is one of the major cellular antioxidant defense systems. To study the effect of age on the regulation of MnSOD in the vasculature, we compared MnSOD expression and its transcriptional regulation in explanted vascular smooth muscle cells (VSMC) isolated from old (24 months old) versus young (6 months old) rats and grown in a normal (5 mM) or high (12.5 and 25 mM) glucose or tumor necrosis factor (5 ng/ml) environment to induce oxidative stress. Both MnSOD protein and activity were reduced in VSMC from old compared with young animals. FOXO3a, a member of the family of Forkhead transcription factors, interacted with the promoter of the rat MnSOD gene at a specific binding site. Inhibition of FOXO3a transcription with small interfering RNA led to a reduction in MnSOD gene expression. VSMC from old rats had increased phosphorylated FOXO3a at Ser²⁵³, which paralleled the reduction of MnSOD protein. Treatment of VSMC with 5 nM insulin-like growth factor-1 induced phosphorylation of Akt and FOXO3a over time, repressing FOXO3a DNA binding and consequently MnSOD gene expression. Furthermore, Akt activity was selectively increased in VSMC from the old, supporting the hypothesis that increased age-related Akt activity might be responsible for the phosphorylation and inactivation of FOXO3a, which in turn down-regulates MnSOD transcription.

Received for publication, July 11, 2006 , and in revised form, October 5, 2006.

^* This work was supported by National Institutes of Health Grants NIA AG00947, AG21106, and NHLBI HL067004. 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.

¹ Present address: Department of Anatomy, The University of Hong Kong.

² To whom correspondence should be addressed: Dept. of Medicine, 89 Beaumont Ave., Given Bldg., Rm. C207, Burlington, VT 05405. Tel.: 802-656-4403; Fax: 802-656-2636; E-mail: naomi.fukagawa{at}uvm.edu.

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