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 A (TxA) mimetics, significantly reduced phosphorylations of endothelial nitric oxide synthase (eNOS) at Ser and Akt at Ser. 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 Ser/Thr 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-Ser/Thr phosphorylation, and dephosphorylation of Akt (at Ser) and eNOS (at Ser). 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.