Activation of thromboxane A2 receptors mediates endothelial dysfunction in diabetic mice.
BACKGROUND
Diabetes is one of high-risk factors for cardiovascular disease. Improvement of endothelial dysfunction in diabetes reduces vascular complications. However, the underlying mechanism needs to be uncovered. This study was conducted to elucidate whether and how thromboxane A2 receptor (TPr) activation contributes to endothelial dysfunction in diabetes.


METHODS AND RESULTS
Exposure of human umbilical vein endothelial cells (HUVECs) to either TPr agonists, two structurally related thromboxane A2 (TxA2) mimetics, significantly reduced phosphorylations of endothelial nitric oxide synthase (eNOS) at Ser1177 and Akt at Ser473. These effects were abolished by pharmacological or genetic inhibitors of TPr. TPr-induced suppression of eNOS and Akt phosphorylation was accompanied by upregulation of PTEN (phosphatase and tension homolog deleted on chromosome 10) and Ser380/Thr382/383 PTEN phosphorylation. PTEN-specific siRNA restored Akt-eNOS signaling in the face of TPr activation. The small GTPase, Rho, was also activated by TPr stimulation, and pretreatment of HUVECs with Y27632, a Rho-associated kinase (ROCK) inhibitor, rescued TPr-impaired Akt-eNOS signaling. In mice, streptozotocin-induced diabetes was associated with aortic PTEN upregulation, PTEN-Ser380/Thr382/383 phosphorylation, and dephosphorylation of Akt (at Ser473) and eNOS (at Ser1177). Importantly, administration of TPr antagonist blocked these changes.


CONCLUSION
We conclude that TPr activation impairs endothelial function by selectively inactivating the ROCK-PTEN-Akt-eNOS pathway in diabetic mice.
['Xie|Xiaona|X|', 'Sun|Wanchun|W|', 'Wang|Jun|J|', 'Li|Xiaoou|X|', 'Liu|Xiaofeng|X|', 'Liu|Ning|N|']
D000577:Amides D000818:Animals D002478:Cells, Cultured D003921:Diabetes Mellitus, Experimental D004730:Endothelium, Vascular D020868:Gene Silencing D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D006973:Hypertension D008297:Male D051379:Mice D052250:Nitric Oxide Synthase Type III D051059:PTEN Phosphohydrolase D010766:Phosphorylation D051057:Proto-Oncogene Proteins c-akt D011725:Pyridines D044244:Receptors, Thromboxane A2, Prostaglandin H2 D015398:Signal Transduction D015854:Up-Regulation D054460:rho-Associated Kinases
thromboxane A2 receptor endothelial dysfunction eNOS Akt PTEN