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Withdrawal: Thromboxane A
- Source :
- The Journal of biological chemistry. 294(37)
- Publication Year :
- 2019
-
Abstract
- This study was conducted to elucidate the molecular mechanisms of thromboxane A2 receptor (TP)-induced insulin resistance in endothelial cells. Exposure of human umbilical vein endothelial cells (HUVECs) or mouse aortic endothelial cells to either IBOP or U46619, two structurally related thromboxane A 2 mimetics, significantly reduced insulin-stimulated phosphorylation of endothelial nitric-oxide synthase (eNOS) at Ser 1177 and Akt at Ser 473 . These effects were abolished by pharmacological or genetic inhibitors of TP. TP-induced suppression of both eNOS and Akt phosphorylation was accompanied by up-regulation of PTEN (phosphatase and tension homolog deleted on chromosome 10), Ser 380 /Thr 382/383 PTEN phosphorylation, and PTEN lipid phosphatase activity. PTEN-specific small interference RNA restored insulin signaling in the face of TP activation. The small GTPase, Rho, was also activated by TP stimulation, and pretreatment of HUVECs with Y27632, a Rho-associated kinase inhibitor, rescued TP-impaired insulin signaling. Consistent with this result, pertussis toxin abrogated IBOP-induced dephosphorylation of both Akt and eNOS, implicating the G i family of G proteins in the suppressive effects of TP. In mice, high fat diet-induced diabetes was associated with aortic PTEN up-regulation, PTEN-Ser 380 /Thr 382/383 phosphorylation, and dephosphorylation of both Akt (at Ser 473 ) and eNOS (at Ser 1177 ). Importantly, administration of TP antagonist blocked these changes. We conclude that TP stimulation impairs insulin signaling in vascular endothelial cells by selectively activating the Rho/Rho-associated kinase/literKB1/PTEN pathway.
- Subjects :
- Male
medicine.medical_specialty
Nitric Oxide Synthase Type III
Thromboxane
AMP-Activated Protein Kinases
Protein Serine-Threonine Kinases
Ligands
Biochemistry
Receptors, Thromboxane A2, Prostaglandin H2
Dephosphorylation
Mice
AMP-Activated Protein Kinase Kinases
Biomimetic Materials
Internal medicine
medicine
Animals
Humans
Insulin
PTEN
Withdrawals/Retractions
Phosphorylation
RNA, Small Interfering
Molecular Biology
Protein kinase B
Cells, Cultured
rho-Associated Kinases
Base Sequence
biology
Chemistry
Kinase
Mechanisms of Signal Transduction
PTEN Phosphohydrolase
Endothelial Cells
Cell Biology
Bridged Bicyclo Compounds, Heterocyclic
Dietary Fats
Mice, Inbred C57BL
Insulin receptor
Endocrinology
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Lipid phosphatase activity
Fatty Acids, Unsaturated
biology.protein
Proto-Oncogene Proteins c-akt
Signal Transduction
Subjects
Details
- ISSN :
- 1083351X
- Volume :
- 294
- Issue :
- 37
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....aaf8f4213edd5a4376a675ed187d32ee