Kaempferol-induced GPER upregulation attenuates atherosclerosis via the PI3K/AKT/Nrf2 pathway

Abstract

Context The effect of kaempferol, a regulator of oestrogen receptors, on atherosclerosis (AS) and the underlying mechanism is elusive. Objective To explore the effect and mechanism of kaempferol on AS. Methods and materials In vivo , C57BL/6 and apolipoprotein E (APOE) –/– mice were randomly categorized into six groups (C57BL/6: control, ovariectomy (OVX), high-fat diet (HFD); APOE –/– : OVX-HFD, OVX-HFD + kaempferol (50 mg/kg) and OVX-HFD + kaempferol (100 mg/kg) and administered with kaempferol for 16 weeks, intragastrically. Oil-Red and haematoxylin–eosin (HE) staining were employed to examine the effect of kaempferol. In vitro , human aortic endothelial cells (HAECs) were pre-treated with or without kaempferol (5, 10 or 20 μM), followed by administration with kaempferol and oxidized low-density lipoprotein (ox-LDL) (200 μg/mL). The effect of kaempferol was evaluated using flow cytometry, and TdT-mediated dUTP Nick-End Labelling (TUNEL). Results In vivo , kaempferol (50 and 100 mg/kg) normalized the morphology of blood vessels and lipid levels and suppressed inflammation and apoptosis. It also activated the G protein-coupled oestrogen receptor (GPER) and PI3K/AKT/nuclear factor-erythroid 2-related factor 2 (Nrf2) pathways. In vitro , ox-LDL (200 μg/mL) reduced the cell viability to 50% (IC 50 ). Kaempferol (5, 10 or 20 μM) induced-GPER activation increased cell viability to nearly 10%, 19.8%, 30%, and the decreased cellular reactive oxygen species (ROS) generation (16.7%, 25.6%, 31.1%), respectively, consequently attenuating postmenopausal AS. However, the protective effects of kaempferol were blocked through co-treatment with si-GPER. Conclusions The beneficial effects of kaempferol against postmenopausal AS are associated with the PI3K/AKT/Nrf2 pathways, mediated by the activation of GPER.

G-Protein-Coupled Estrogen Receptor Expression in Rat Uterine Artery Is Increased by Pregnancy and Induces Dilation in a Ca2+ and ERK1/2 Dependent Manner

“…The following supporting information can be downloaded at: . References [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 ] are cited in Supplementary Materials.…”

Ginsenoside Rc attenuates myocardial ischaemic injury through antioxidative and anti-inflammatory effects

“…It is supposed that Nrf2 and NF-κB signalling pathways may interact to regulate the cellular response to myocardial ischaemia (Feng et al. 2021 ). However, this study did not investigate the interplay of Nrf2 and NF-kB in the cardioprotective effect of ginsenoside Rc.…”

Theaflavin Attenuates TBHP-Induced Endothelial Cells Oxidative Stress by Activating PI3K/AKT/Nrf2 and Accelerates Wound Healing in Rats

“…AKT is a serine/threonine kinase and a downstream signal molecule of PI3K, activated by it ( Li et al, 2017 ). Several studies have reported that the PI3K/Akt pathway is essential for regulating Nrf2/Ho-1 pathway activation and is thus involved in protection against oxidative stress and apoptosis in multiple cell types ( Di Tu et al, 2020 ; Feng et al, 2021 ; Wu et al, 2021 ). Under oxidative stress, the PI3K/Akt signaling pathway leads to Nrf2-dependent transcription and overexpression of HO-1 protein ( He et al, 2019 ).…”