Quercetin Prevents In Vivo and In Vitro Myocardial Hypertrophy Through the Proteasome-GSK-3 Pathway
- 224 Downloads
Quercetin, a flavonoid, has been reported to ameliorate cardiovascular diseases, such as cardiac hypertrophy. However, the mechanism is not completely understood. In this study, a mechanism related to proteasome-glycogen synthesis kinase 3 (GSK-3) was elucidated in rats and primary neonatal cardiomyocytes.
Rats were subjected to sham or constriction of abdominal aorta surgery groups and treated with or without quercetin for 8 weeks. Angiotensin II (Ang II)-induced primary cardiomyocytes were cultured with quercetin treatment or not for 48 h. Echocardiography, real-time RT-PCR, histology, immunofluorescence, and Western blotting were conducted. Proteasome activities were also detected using a fluorescent peptide substrate.
Echocardiography showed that quercetin prevented constriction of abdominal aorta-induced cardiac hypertrophy and improved the cardiac diastolic function. In addition, quercetin also significantly reduced the Ang II-induced hypertrophic surface area and atrial natriuretic factor (ANF) mRNA level in primary cardiomyocytes. Proteasome activities were obviously inhibited in the quercetin-treated group both in vivo and in vitro. Quercetin also decreased the levels of proteasome subunit beta type (PSMB) 1, PSMB2, and PSMB5 of the 20S proteasome as well as the levels of proteasome regulatory particle (Rpt) 1 and Rpt4 of the 19S proteasome. In particular, the PSMB5 level in the nucleus was reduced after quercetin treatment. Furthermore, phosphorylated GSK-3α/β (inactivation of GSK-3) was decreased, which means that GSK-3 activity was increased. The phosphorylation levels of upstream AKT (PKB (protein kinase B)) and liver kinase B1/AMP activated protein kinase (LKB1/AMPKα) and those of downstream extracellular signal-regulated kinase (ERK), histone H3, β-catenin, and GATA binding protein 4 (GATA4) were reduced after quercetin treatment, while hypertrophy was reversed after treatment with the GSK-3 inhibitor.
In summary, quercetin prevents cardiac hypertrophy, which is related to proteasome inhibition and activation of GSK-3α/β. Upstream (AKT, LKB1/AMPKα) and downstream hypertrophic factors, such as ERK, histone H3, β-catenin, and GATA4, may also be involved.
KeywordsMyocardial hypertrophy Quercetin Proteasome inhibition GSK-3
This study was funded by grants from the National Natural Science Foundation of China (30901806 to YH. Liu), Natural Science Foundation of Guangdong Province (2014A030313485 to YH. Liu), Outstanding Young Teachers Training Plan in Higher Education Institutions of Guangdong Province (B16036028 to YH. Liu), Scientific and Technological Planning Program of Guangzhou (2017071010458 to YH. Liu), Municipal Education Bureau Program of Guangzhou (1201610286 to YH. Liu), Outstanding Young Teachers Training Plan in Higher Education Institutions of Guangdong Province (YQ2015137 to Q. Xue), Municipal Education Bureau Program of Guangzhou (1201410365 to Q. Xue), and Scientific and Technological Planning Program of Guangdong Province (2014A020212361, Q. Xiao).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
All procedures involving animal experimentation were performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health (USA). The animal use protocol was approved by the Committee on the Ethics of Animal Experiments of Guangzhou Medical University and the approval reference number was SCXK 2013-0002.
- 2.Tarone G, Balligand JL, Bauersachs J, Clerk A, De Windt L, Heymans S, et al. Targeting myocardial remodelling to develop novel therapies for heart failure: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology. Eur J Heart Fail. 2014;16(5):494–508.CrossRefPubMedGoogle Scholar
- 14.Yan L, Zhang JD, Wang B, Lv YJ, Jiang H, Liu GL, et al. Quercetin inhibits left ventricular hypertrophy in spontaneously hypertensive rats and inhibits angiotensin II-induced H9C2 cells hypertrophy by enhancing PPAR-gamma expression and suppressing AP-1 activity. PLoS One. 2013;8(9):e72548.CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Arioka M, Takahashi-Yanaga F, Sasaki M, Yoshihara T, Morimoto S, Takashima A, et al. Acceleration of bone development and regeneration through the Wnt/beta-catenin signaling pathway in mice heterozygously deficient for GSK-3beta. Biochem Biophys Res Commun. 2013;440(4):677–82.CrossRefPubMedGoogle Scholar