Abstract
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.
Highlights
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
Resistin Inhibited endothelial nitric-oxide synthase (eNOS) Activation—To determine whether resistin has any effect on eNOS activation, we first examined the effects of resistin on eNOS activity by measuring the conversion of L-[3H]arginine to L-[3H]citrulline in resistin-treated cells
We examined whether this reduced eNOS activity was due to reduced eNOS activation by resistin treatment. eNOS can be activated by phosphorylation at Ser-1177 and dephosphorylation at Thr-495 by multiple protein kinases and phosphatases [29]
Summary
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). An adipokine/cytokine, is involved in inflammatory processes that could lead to insulin resistance status and vascular diseases. We observed that resistin inhibited insulin signaling and eNOS activation in endothelial cells. Up-regulation of PTEN is involved in the inhibitory effects of resistin on insulin signaling and eNOS activation in endothelial cells. Our findings suggest that resistin-mediated inhibition of insulin signaling and eNOS activation may contribute to cardiovascular diseases. It has become clear that inflammatory factors can inhibit the IRS/PI3K/PDK/Akt pathway and lead to insulin resistance [11]. Increasing evidence suggests that resistin may be involved in the inflammatory process, which is a common feature in metabolic syndrome, insulin resistance status, and vascular diseases. Consistent with the hypothesis that resistin plays a role in the inflammatory process, recent studies have shown that resistin is abun-
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