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J. Biol. Chem., Vol. 281, Issue 12, 7727-7736, March 24, 2006

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Up-regulation of PTEN (Phosphatase and Tensin Homolog Deleted on Chromosome Ten) Mediates p38 MAPK Stress Signal-induced Inhibition of Insulin Signaling

A CROSS-TALK BETWEEN STRESS SIGNALING AND INSULIN SIGNALING IN RESISTIN-TREATED HUMAN ENDOTHELIAL CELLS^*

From the Section of Adult Cardiac Surgery, the Texas Heart Institute at St. Luke's Episcopal Hospital and the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030

The key feature of metabolic syndrome, a cluster of metabolic and cardiovascular disorders, is systemic insulin resistance, which is associated with dysregulated endothelial nitric-oxide synthase (eNOS). Stress signaling induced by inflammation can inhibit insulin signaling. However, molecular mechanisms for the cross-talk between stress signaling and insulin resistance are only partially understood. Resistin, an adipokine/cytokine, is involved in inflammatory processes that could lead to insulin resistance status and vascular diseases. In the current study, we observed that resistin inhibited insulin signaling and eNOS activation in endothelial cells. Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) expression by resistin may mediate the inhibitory effects. Activated stress signaling p38 MAPK, but not JNK, is involved in PTEN up-regulation. We further found that p38 target transcriptional factor activating transcription factor-2 (ATF-2) bound to ATF sites in the PTEN promoter. The phosphorylation/activation of ATF-2 and its binding to PTEN promoter were increased by resistin treatment. In summary, up-regulation of PTEN is involved in the inhibitory effects of resistin on insulin signaling and eNOS activation in endothelial cells. Resistin induces PTEN expression by activating stress signaling p38 pathway, which may activate target transcription factor ATF-2, which in turn induces PTEN expression. Our findings suggest that resistin-mediated inhibition of insulin signaling and eNOS activation may contribute to cardiovascular diseases.

Received for publication, October 12, 2005 , and in revised form, December 23, 2005.

^* This work was supported by American Heart Association Grants TX0565134Y (to Y. H. S.) and by National Institutes of Health Grants R01-HL071608 and R01-HL066053 (to X. L. W.). 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 To whom correspondence may be addressed: Division of Cardiothoracic Surgery, Baylor College of Medicine, NAB 2010, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-8406; Fax: 713-798-1705; E-mail: hyshen{at}bcm.tmc.edu. ² To whom correspondence may be addressed: Division of Cardiothoracic Surgery, Baylor College of Medicine, NAB 2010, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-5485; Fax: 713-798-1705; E-mail: xlwang{at}bcm.tmc.edu.

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