Activation of thromboxane A2 receptors mediates endothelial dysfunction in diabetic mice

ABSTRACT

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/Thr^382/383 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/Thr^382/383 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.

KEYWORDS:

• Akt
• eNOS
• endothelial dysfunction
• PTEN
• thromboxane A2 receptor

Declaration of interest

None.

Funding

This work was supported by National Natural Science Foundation of China (grant numbers 81472030, 81202207, 21175055, and 81673168), Natural Science Foundation of Jilin Provincial Science and Technology Department, China (grant numbers 20110739 and 20150204001YY), Jilin University Bethune Project B (grant number 2012210), and Health and Family Planning Commission of Jilin Province (grant number 2015Z041).

Additional information

Funding

This work was supported by National Natural Science Foundation of China (grant numbers 81472030, 81202207, 21175055, and 81673168), Natural Science Foundation of Jilin Provincial Science and Technology Department, China (grant numbers 20110739 and 20150204001YY), Jilin University Bethune Project B (grant number 2012210), and Health and Family Planning Commission of Jilin Province (grant number 2015Z041).