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.
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.
Shen
Ying H
YH
Section of Adult Cardiac Surgery, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, Texas 77030, USA. hyshen@bcm.tmc.edu
Zhang
Lin
L
Gan
Yehua
Y
Wang
Xinwen
X
Wang
Jian
J
LeMaire
Scott A
SA
Coselli
Joseph S
JS
Wang
Xing Li
XL
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D001011:Aorta / Q000378:metabolism; D001665:Binding Sites; D015153:Blotting, Western; D002318:Cardiovascular Diseases / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D015233:Models, Statistical; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D052243:Resistin / Q000737:chemistry / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D007328:Insulin; D034741:RNA, Small Interfering; D052243:Resistin; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase