Omentin-1 protects against high glucose-induced endothelial dysfunction via the AMPK/PPARδ signaling pathway

• Published in: Biochemical pharmacology Vol. 174; p. 113830
• Main Authors: Liu, Fang, Fang, Shaohong, Liu, Xinxin, Li, Ji, Wang, Xuedong, Cui, Jinjin, Chen, Tao, Li, Zhaoying, Yang, Fan, Tian, Jiangtian, Li, Hulun, Yin, Li, Yu, Bo
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.04.2020
• Subjects: AMP-activated protein kinase; Endothelial dysfunction; High glucose; Omentin-1; Peroxisome proliferator-activated receptor δ; Endothelial dysfunction; Omentin-1; AMP-activated protein kinase; Peroxisome proliferator-activated receptor δ; High glucose
• DOI: 10.1016/j.bcp.2020.113830
• ISSN: 0006-2952; 1873-2968

[Display omitted] High glucose-induced endothelial dysfunction is a critical initiating factor in the development of diabetic vascular complications. Omentin-1 has been regarded as a novel biomarker of endothelial function in subjects with type-2 diabetes (T2D); however, it is unclear whether omentin-1 has any direct effect in ameliorating high glucose-induced endothelial dysfunction. In the present study, we analyzed the effect of omentin-1 on high glucose-induced endothelial dysfunction in isolated mouse aortas and mouse aortic endothelial cells (MAECs). Vascular reactivity in aortas was measured using wire myography. The expression levels of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor δ (PPARδ), Akt, endothelial nitric-oxide synthase (eNOS), and endoplasmic reticulum (ER)-stress markers in MAECs were determined by Western blotting. The production of reactive oxygen species (ROS) and nitric oxide (NO) was assessed by diluted fluoroprobe, 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) and 4-amino-5-methylamino-2′,7′-difluorofluorescein (DAF-FM DA), respectively. We found that ex vivo treatment with omentin-1 reversed impaired endothelial-dependent relaxations (EDR) in mouse aortas after high-glucose insult. Elevated ER-stress markers, oxidative stress, and reduction of NO production induced by high glucose in MAECs were reversed by omentin-1 treatment. Omentin-1 also effectively reversed tunicamycin-induced ER stress responses in MAECs, as well as ameliorated impairment of endothelial-dependent relaxation in mouse aortas. Moreover, omentin-1 increased AMPK phosphorylation with a subsequent increase in PPARδ expression, while also restoring the decreased phosphorylation of Akt and eNOS. The effects of omentin-1 were abolished by cotreatment of compound C (AMPK inhibitor) and GSK0660 (PPARδ antagonist). These data indicate that omentin-1 protects against high glucose-induced vascular-endothelial dysfunction through inhibiting ER stress and oxidative stress and increasing NO production via activation of AMPK/PPARδ pathway.