Abstract
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. 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/T...Continue Reading
References
Apr 7, 1995·Cell·C D Nobes, A Hall
Aug 1, 1996·Diabetes·T UtsugiP Santamaria
Mar 24, 1999·The Journal of Cell Biology·C D Nobes, A Hall
Jun 22, 1999·Nature·D FultonW C Sessa
Jun 22, 1999·Nature·S DimmelerA M Zeiher
Aug 15, 2000·Journal of Cardiovascular Pharmacology·M J MihmJ A Bauer
Oct 31, 2000·Circulation Research·Y GaoJ A Ware
Nov 26, 2002·Molecular and Cellular Biology·Xiu-Fen MingZhihong Yang
Jul 10, 2004·Circulation Research·Anthony W Ashton, J Anthony Ware
Apr 19, 2005·Nature Medicine·Koji TakayamaFumitaka Ushikubi
Nov 2, 2005·Circulation·Adriana ZuccolloRichard A Cohen
Feb 7, 2006·Cardiovascular Research·Arántzazu AlfrancaJuan Miguel Redondo
Jul 29, 2006·Diabetes·Xing Li WangYing H Shen
Nov 11, 2006·Circulation Research·Anju NohriaMark A Creager
Jul 2, 2008·Cardiovascular Research·Shuangxi WangLiying Liu
Aug 23, 2008·Nature Reviews. Molecular Cell Biology·Sarah J Heasman, Anne J Ridley
Jun 17, 2009·Diabetes·Shuangxi WangMing-Hui Zou
Feb 20, 2010·Circulation Research·Shuangxi WangMing-Hui Zou
Apr 6, 2011·Hypertension·Shuangxi WangMing-Hui Zou
May 9, 2012·Nature Medicine·Shuangxi WangMing-Hui Zou
Jan 31, 2013·European Journal of Clinical Nutrition·N J Kellow, G S Savige
Mar 2, 2013·Current Pharmaceutical Design·Teresa Vanessa FiorentinoFranco Folli
Jan 1, 2014·The Review of Diabetic Studies : RDS·Sandra J Hamilton, Gerald F Watts
May 2, 2014·Current Atherosclerosis Reports·Francesco PaneniFrancesco Cosentino
Jan 8, 2015·Journal of Exercise Nutrition & Biochemistry·Moon-Hyon Hwang, Sangho Kim
Feb 7, 2015·Journal of Cellular and Molecular Medicine·Xu-Hong YangShuang-Xi Wang
Jul 16, 2015·Journal of Cellular and Molecular Medicine·Jie WangShuang-Xi Wang
Dec 24, 2015·Journal of Diabetes Research·Peng LiShuang-Xi Wang
Feb 18, 2016·Journal of Diabetes Research·Zhan LiuShuang-Xi Wang