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Quercetin Prevents In Vivo and In Vitro Myocardial Hypertrophy Through the Proteasome-GSK-3 Pathway
Purpose 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...
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Published in: | Cardiovascular drugs and therapy 2018-02, Vol.32 (1), p.5-21 |
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Main Authors: | , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
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Online Access: | Get full text |
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Summary: | Purpose
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.
Methods
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.
Results
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
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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.
Conclusion
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. |
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ISSN: | 0920-3206 1573-7241 |
DOI: | 10.1007/s10557-018-6771-4 |