Apigenin alleviates diabetic endothelial dysfunction through activating AMPK/PI3K/Akt/eNOS and Nrf2/HO-1 signaling pathways

Abstract

Apigenin (4′,5,7-trihydroxyflavone) is a natural flavone reported to present anti-diabetic and anti-oxidative bioactivities. The effect of apigenin to mitigate endothelial dysfunction in diabetes remains to be investigated. In the present study, the vaso-protective effect of apigenin as well as its underlying action mechanisms was investigated using in vitro- and in vivo-based assays. Aortas were detached from C57BL/6J mice for ex vivo treatment, and primary rat aortic endothelial cells (RAECs) were cultured and further stimulated using high glucose (HG) with or without apigenin. In-vivo diabetic model was established by feeding male C57BL/6J mice with a high-fat diet (60% kcal% fat) for a total of 14 weeks, whereas the treatment group was orally administered apigenin (25 mg/kg/day) during the last 4 weeks. Exposure to HG (30 mM, 48 h) impaired acetylcholine-induced endothelium-dependent relaxation (EDR) in mouse aortas and induced oxidative stress with the downregulation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/phosphatidyl inositol 3-kinase (PI3K)/protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathways in aortas and RAECs. These impairments were reversed by apigenin treatments. However, the vaso-protective effects of apigenin were abolished by Compound C (AMPK inhibitor) and wortmannin (PI3K inhibitor). Chronic oral administration with apigenin ameliorated EDR and reduced oxidative stress in the aortas of high-fat diet (HFD)-induced obese and diabetic mice. In conclusion, this study revealed that apigenin improved endothelial function and suppressed oxidative stress in the vasculature in diabetes through the activation of AMPK/PI3K/Akt/eNOS and Nrf2/HO-1 pathways, suggesting its therapeutic potential as a natural dietary flavonoid against vascular diseases associated with diabetes.