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SET8 suppression mediates high glucose-induced vascular endothelial inflammation via the upregulation of PTEN

Experimental & Molecular Medicine 2020년 52권 10호 p.2 ~ 2
Shen Xuefang, Chen Xiangyuan, Wang Jing, Liu Jing, Wang Zhiyao, Hua Qing, Wu Qichao, Su Yanguang, He Huanzhong, Hu Yuqin, Meng Zhipeng, Xiong Wanxia, Zhu Minmin,
소속 상세정보
 ( Shen Xuefang ) - Fudan University Shanghai Medical College Department of Oncology
 ( Chen Xiangyuan ) - Fudan University Shanghai Medical College Department of Oncology
 ( Wang Jing ) - Fudan University Shanghai Medical College Department of Oncology
 ( Liu Jing ) - Huzhou University Huzhou Central Hospital Department of Anaesthesiology
 ( Wang Zhiyao ) - Fudan University Zhongshan Hospital Department of Anesthesia
 ( Hua Qing ) - Fudan University Shanghai Medical College Department of Oncology
 ( Wu Qichao ) - Fudan University Shanghai Medical College Department of Oncology
 ( Su Yanguang ) - Huzhou Maternal and Child Health Care Hospital Department of Anaesthesiology
 ( He Huanzhong ) - Huzhou Maternal and Child Health Care Hospital Department of Anaesthesiology
 ( Hu Yuqin ) - Huzhou Maternal and Child Health Care Hospital Department of Anaesthesiology
 ( Meng Zhipeng ) - Huzhou University Huzhou Central Hospital Department of Anaesthesiology
 ( Xiong Wanxia ) - Fudan University Zhongshan Hospital Department of Anesthesia
 ( Zhu Minmin ) - Fudan University Shanghai Medical College Department of Oncology

Abstract


Hyperglycemia-mediated endothelial inflammation participates in the pathogenesis of cardiovascular complications in subjects with diabetes. Previous studies reported that phosphatase and tensin homolog deleted on chromosome ten (PTEN) and SET8 participate in high glucose-mediated endothelial inflammation. In this study, we hypothesize that SET8 regulates PTEN expression, thus contributing to high glucose-mediated vascular endothelial inflammation. Our data indicated that plasma soluble intercellular adhesion molecule-1 (sICAM-1) and endothelial selectin (e-selectin) were increased in patients with diabetes and diabetic rats. PTEN expression was augmented in the peripheral blood mononuclear cells of patients with diabetes and in the aortic tissues of diabetic rats. Our in vitro study indicated that high glucose increased monocyte/endothelial adhesion, endothelial adhesion molecule expression and p65 phosphorylation in human umbilical vein endothelial cells (HUVECs). Moreover, high glucose led to endothelial inflammation via upregulation of PTEN. Furthermore, high glucose inhibited SET8 expression and histone H4 lysine 20 methylation (H4K20me1), a downstream target of SET8. SET8 overexpression reversed the effects of high-glucose treatment. shSET8-mediated endothelial inflammation was counteracted by siPTEN. Furthermore, SET8 was found to interact with FOXO1. siFOXO1 attenuated high glucose-mediated endothelial inflammation. FOXO1 overexpression-mediated endothelial inflammation was counteracted by siPTEN. H4K20me1 and FOXO1 were enriched in the PTEN promoter region. shSET8 increased PTEN promoter activity and augmented the positive effect of FOXO1 overexpression on PTEN promoter activity. Our in vivo study indicated that SET8 was downregulated and FOXO1 was upregulated in the peripheral blood mononuclear cells of patients with diabetes and the aortic tissues of diabetic rats. In conclusion, SET8 interacted with FOXO1 to modulate PTEN expression in vascular endothelial cells, thus contributing to hyperglycemia-mediated endothelial inflammation.

키워드

Diabetes complications; Vascular diseases

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