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Quercetin Prevents In Vivo and In Vitro Myocardial Hypertrophy Through the Proteasome-GSK-3 Pathway
- Source :
- Cardiovascular drugs and therapy. 32(1)
- Publication Year :
- 2018
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
Proteasome Endopeptidase Complex
030204 cardiovascular system & hematology
Pharmacology
Ventricular Function, Left
Rats, Sprague-Dawley
03 medical and health sciences
Glycogen Synthase Kinase 3
0302 clinical medicine
AMP-activated protein kinase
GSK-3
Medicine
Animals
heterocyclic compounds
Pharmacology (medical)
Myocytes, Cardiac
Phosphorylation
Protein kinase B
Cells, Cultured
PSMB2
Glycogen Synthase Kinase 3 beta
biology
Ventricular Remodeling
Kinase
business.industry
General Medicine
Angiotensin II
PSMB5
Disease Models, Animal
030104 developmental biology
cardiovascular system
biology.protein
Hypertrophy, Left Ventricular
Quercetin
Cardiology and Cardiovascular Medicine
business
Proteasome Inhibitors
Proteasome regulatory particle
Signal Transduction
Subjects
Details
- ISSN :
- 15737241
- Volume :
- 32
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Cardiovascular drugs and therapy
- Accession number :
- edsair.doi.dedup.....52f3228eb05409cb37f8cfaa233f96d2