Kaempferol-induced GPER Upregulation Attenuates Atherosclerosis Via the PI3K/AKT/Nrf2 Pathway

Overview

Journal Pharm Biol

Specialties Pharmacology
Pharmacy

Date 2021 Aug 17

PMID 34403325

Citations 37

Authors

Zhuo Feng

Changyuan Wang

Yue

Jin

Qiang Meng

Jingjing Wu

Huijun Sun

Affiliations

Soon will be listed here.

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: , 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. , 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: , 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. , ox-LDL (200 μg/mL) reduced the cell viability to 50% (IC). 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.

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References

Xu Y, Han F, Tan J . Edaravone protects the retina against ischemia/reperfusion‑induced oxidative injury through the PI3K/Akt/Nrf2 pathway. Mol Med Rep. 2017; 16(6):9210-9216. DOI: 10.3892/mmr.2017.7739. View

Aryan L, Younessi D, Zargari M, Banerjee S, Agopian J, Rahman S . The Role of Estrogen Receptors in Cardiovascular Disease. Int J Mol Sci. 2020; 21(12). PMC: 7352426. DOI: 10.3390/ijms21124314. View

Wu P, Meng X, Zheng H, Zeng Q, Chen T, Wang W . Kaempferol Attenuates ROS-Induced Hemolysis and the Molecular Mechanism of Its Induction of Apoptosis on Bladder Cancer. Molecules. 2018; 23(10). PMC: 6222750. DOI: 10.3390/molecules23102592. View

Okuyama H, Langsjoen P, Hamazaki T, Ogushi Y, Hama R, Kobayashi T . Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Expert Rev Clin Pharmacol. 2015; 8(2):189-99. DOI: 10.1586/17512433.2015.1011125. View

Pollard K, Daniel J . Nuclear estrogen receptor activation by insulin-like growth factor-1 in Neuro-2A neuroblastoma cells requires endogenous estrogen synthesis and is mediated by mutually repressive MAPK and PI3K cascades. Mol Cell Endocrinol. 2019; 490:68-79. PMC: 6520186. DOI: 10.1016/j.mce.2019.04.007. View

Thangapandiyan S, Ramesh M, Hema T, Miltonprabu S, Uddin M, Nandhini V . Sulforaphane Potentially Ameliorates Arsenic Induced Hepatotoxicity in Albino Wistar Rats: Implication of PI3K/Akt/Nrf2 Signaling Pathway. Cell Physiol Biochem. 2019; 52(5):1203-1222. DOI: 10.33594/000000082. View

Petri M, Laguna-Fernandez A, Arnardottir H, Wheelock C, Perretti M, Hansson G . Aspirin-triggered lipoxin A4 inhibits atherosclerosis progression in apolipoprotein E mice. Br J Pharmacol. 2017; 174(22):4043-4054. PMC: 5659998. DOI: 10.1111/bph.13707. View

Morselli E, Santos R, Criollo A, Nelson M, Palmer B, Clegg D . The effects of oestrogens and their receptors on cardiometabolic health. Nat Rev Endocrinol. 2017; 13(6):352-364. DOI: 10.1038/nrendo.2017.12. View

Schierbeck L . Primary prevention of cardiovascular disease with hormone replacement therapy. Climacteric. 2015; 18(4):492-7. DOI: 10.3109/13697137.2015.1034098. View

10.

Gu L, Ye P, Li H, Wang Y, Xu Y, Tian Q . Lunasin attenuates oxidant-induced endothelial injury and inhibits atherosclerotic plaque progression in ApoE mice by up-regulating heme oxygenase-1 via PI3K/Akt/Nrf2/ARE pathway. FASEB J. 2019; 33(4):4836-4850. DOI: 10.1096/fj.201802251R. View

11.

Yang Q, Wang C, Jin Y, Ma X, Xie T, Wang J . Disocin prevents postmenopausal atherosclerosis in ovariectomized LDLR-/- mice through a PGC-1α/ERα pathway leading to promotion of autophagy and inhibition of oxidative stress, inflammation and apoptosis. Pharmacol Res. 2019; 148:104414. DOI: 10.1016/j.phrs.2019.104414. View

12.

Kim T, Lee S, Kim M, Cheon C, Ko S . Kaempferol induces autophagic cell death via IRE1-JNK-CHOP pathway and inhibition of G9a in gastric cancer cells. Cell Death Dis. 2018; 9(9):875. PMC: 6115440. DOI: 10.1038/s41419-018-0930-1. View

13.

Langasco R, Fancello S, Rassu G, Cossu M, Cavalli R, Galleri G . Increasing protective activity of genistein by loading into transfersomes: A new potential adjuvant in the oxidative stress-related neurodegenerative diseases?. Phytomedicine. 2019; 52:23-31. DOI: 10.1016/j.phymed.2018.09.207. View

14.

Lee Y, Lin H, Fiona Chan Y, Li K, To O, Yan B . Mouse models of atherosclerosis: a historical perspective and recent advances. Lipids Health Dis. 2017; 16(1):12. PMC: 5240327. DOI: 10.1186/s12944-016-0402-5. View

15.

Zhong X, Zhang L, Li Y, Li P, Li J, Cheng G . Kaempferol alleviates ox-LDL-induced apoptosis by up-regulation of miR-26a-5p via inhibiting TLR4/NF-κB pathway in human endothelial cells. Biomed Pharmacother. 2018; 108:1783-1789. DOI: 10.1016/j.biopha.2018.09.175. View

16.

Jing Y, Cai D, Chen Q, Xiong Q, Hu T, Yao Y . Liuwei Dihuang soft capsules attenuates endothelial cell apoptosis to prevent atherosclerosis through GPR30-mediated regulation in ovariectomized ApoE-deficient mice. J Ethnopharmacol. 2017; 208:185-198. DOI: 10.1016/j.jep.2017.06.052. View

17.

Alkhalidy H, Moore W, Wang Y, Luo J, McMillan R, Zhen W . The Flavonoid Kaempferol Ameliorates Streptozotocin-Induced Diabetes by Suppressing Hepatic Glucose Production. Molecules. 2018; 23(9). PMC: 6192519. DOI: 10.3390/molecules23092338. View

18.

Fredman G, Tabas I . Boosting Inflammation Resolution in Atherosclerosis: The Next Frontier for Therapy. Am J Pathol. 2017; 187(6):1211-1221. PMC: 5455064. DOI: 10.1016/j.ajpath.2017.01.018. View

19.

Jian X, Liu Y, Zhao Z, Zhao L, Wang D, Liu Q . The role of traditional Chinese medicine in the treatment of atherosclerosis through the regulation of macrophage activity. Biomed Pharmacother. 2019; 118:109375. DOI: 10.1016/j.biopha.2019.109375. View

20.

Zhang K, Zhang Y, Zhang M, Gu L, Liu Z, Jia J . Effects of phospholipid complexes of total flavonoids from Persimmon (Diospyros kaki L.) leaves on experimental atherosclerosis rats. J Ethnopharmacol. 2016; 191:245-253. DOI: 10.1016/j.jep.2016.06.043. View