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Hyperglycemia via activation of thromboxane A2 receptor impairs the integrity and function of blood-brain barrier in microvascular endothelial cells

Zhihong Zhao, Jue Hu, Xiaoping Gao, Hui Liang, Haiya Yu, Suosi Liu and Zhan Liu _

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Oncotarget. 2017; 8:30030-30038. https://doi.org/10.18632/oncotarget.16273

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Zhihong Zhao1,*, Jue Hu2,*, Xiaoping Gao1, Hui Liang1, Haiya Yu3, Suosi Liu1,4, Zhan Liu4

1Department of Neurology, The First Affiliated Hospital (People’s Hospital of Hunan Province), Hunan Normal University, Changsha, Hunan, China

2Department of Neurology, Changsha Central Hospital, Changsha, Hunan, China

3Department of Neurology, The People’s Hospital of Xishui, Huangang, Hubei, China

4Department of Clinical Nutrition and Gastroenterology, The First Affiliated Hospital (People’s Hospital of Hunan Province), Hunan Normal University, Changsha, Hunan, China

*These authors contributed equally to this work

Correspondence to:

Zhan Liu, email: [email protected]

Zhihong Zhao, email: [email protected]

Keywords: diabetes, thromboxane A2 receptor, blood-brain barrier

Received: February 04, 2017     Accepted: March 06, 2017     Published: March 16, 2017


Diabetes is one of high risk factors for cardio- and cerebra-vascular diseases, including stroke, atherosclerosis and hypertension. This study was conducted to elucidate whether and how thromboxane receptor (TPr) activation contributes to blood-brain barrier (BBB) dysfunction in diabetes. Human brain microvascular endothelial cells (HBMECs) were cultured. The levels of phosphorylated endothelial nitric oxide synthase (eNOS) at Ser1177 (p-eNOS) and Akt at Ser473 (p-Akt) were assayed by western blot. Exposure of HBMECs to either high glucose (HG) or thromboxane A2 (TxA2) mimetic U46619, significantly reduced p-eNOS and p-Akt. These effects were abolished by pharmacological or genetic inhibitors of TPr. HG/U46619-induced suppressions of eNOS and Akt phosphorylation were accompanied by upregulation of PTEN and Ser380/Thr382/383 PTEN phosphorylation. PTEN-specific siRNA restored Akt-eNOS signaling in the face of TPr activation or HG. The small GTPase, Rho, was also activated by HG stimulation, and pretreatment of HBMECs with Y27632, a Rho-associated kinase (ROCK) inhibitor, rescued HG-impaired Akt-eNOS signaling. In STZ-injected rats, we found that hyperglycemia dramatically increased the levels of PTEN and PTEN-Ser380/Thr382/383 phosphorylation, reduced both levels of p-eNOS and p-Akt, and disrupted BBB function assayed by Evans blue staining, which were abolished by SQ29548 treatment. We conclude that hyperglycemia activates thromboxane A2 receptor to impair the integrity and function of blood-brain barrier via the ROCK-PTEN-Akt-eNOS pathway.

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