Quercetin improves heart failure by inhibiting cardiomyocyte apoptosis via suppressing the MAPK signaling pathway

doi:10.12122/j.issn.1673-4254.2025.01.22

Abstract

Abstract:

Objective To explore the mechanism that mediate the therapeutic effect of quercetin on heart failure. Methods We searched the TCMSP and Swiss ADME databases for the therapeutic targets of quercetin and retrieved heart failure targets from the Genecards and OMIM databases. The intersecting targets were analyzed with GO and KEGG pathway analysis using DAVID database, and the key genes were identified via PPI analysis. Molecular docking between the core targets and quercetin was performed using PyMOL and AutoDock Tools. In a heart failure model established in H9C2 cardiomyocytes by treatment with isoproterenol, the effect of quercetin on the expressions of the MAPK signaling pathway was tested. Results A total of 60 intersecting targets were identified. Enrichment analysis revealed that quercetin may inhibit heart failure through the MAPK signaling pathway. The core genes, including AMPK3 and BCL-2, were identified as potential key regulators in quercetin-mediated improvement of heart failure. Cellular experiments demonstrated that quercetin significantly reduced isoproterenol-induced apoptosis of cardiomyocytes in a dose-dependent manner and obviously decreased the Bax/Bcl-2 ratio and the expression levels of caspase-3, ERK and p38 in the cells. Conclusion Quercetin improves heart failure possibly by inhibiting cardiomyocyte apoptosis through the MAPK signaling pathway.

Key words: quercetin, heart failure, isoproterenol, MAPK, network pharmacology

Xiupeng LONG, Shun TAO, Shen YANG, Suyun LI, Libing RAO, Li LI, Zhe ZHANG. Quercetin improves heart failure by inhibiting cardiomyocyte apoptosis via suppressing the MAPK signaling pathway[J]. Journal of Southern Medical University, 2025, 45(1): 187-196.

Figures/Tables 10

Tab.1 Primer sequence for qRT-PCR

Genes	Primer sequence
Bcl-2	F: 5'-ATCTCCCTGTTGACGCTCT-3′
	R: 5'-CATCTTCTCCTTCCAGCCT-3′
Bax	F: 5'-AGCCACAAAGATGGTCACT-3′
	R: 5'-GGAGATGAACTGGATAGCAA-3′
Caspase-3	F: 5'-TGTTTCCCTGAGGTTTGCTG-3′
	R: 5'-TGCTATTGTGAGGCGGTTGT-3′
ERK	F: 5'-CGGAACTTGCAATCCTCAGT-3′
	R: 5'-TCGTGTGGGTCCTGAATTGG-3′
p38	F: 5'-CTGCGAGGGCTGAAGTAT-3′
	R: 5'-TCCTCTTATCCGAGTCCAA-3′
GAPDH	F: 5'-GAAGGTGAAGGTCGGAGTC-3'
	R: 5'-GAAGATGGTGATGGGATTTC-3'

Fig.1 Intersection targets of quercetin and heart failure. Que: Quercetin; HF: Heart failure.

Fig.2 Core genes of quercetin for treatment of heart failure.

Fig.4 Molecular docking results of the core targets with quercetin.

Fig.5 Effects of different concentrations of quercetin on survival rate of H9C2 cardiomyocytes. **P<0.01 vs 0 μmol/L group (n=5).

Fig.6 Effects of different concentrations of quercetin(Que) on isoproterenol (ISO)-induced injury in mouse cardiomyocytes. A: Effects of different concentrations of quercetin on the survival rate of myocardial cells induced by ISO. B: Hoechst staining for detecting apoptosis of the injured cardiomyocytes (Original magnification:×200). ##P<0.01 vs Control group, *P<0.05, **P<0.01 vs ISO group (n=3).

Fig.8 Effects of different concentrations of quercetin on mRNA expressions of Bcl-2 (A), Bax (B), Bax/Bcl-2 ratio (C) and caspase-3 (D) in the cardiomyocytes in each group. ##P<0.01 vs Control group, *P<0.05, **P<0.01 vs ISO group (n=3).

Fig.9 Effects of different concentrations of quercetin on the expression of apoptosis-related proteins in the cardiomyocytes in each group. A: Western blotting of c-caspase-3, t-caspase-3, Bcl-2 and Bax proteins. B: Ratio of cleaved-caspase-3/caspase-3 protein. C: Ratio of Bax/Bcl-2 protein. ##P<0.01 vs Control group, **P<0.01 vs ISO group (n=3).

Fig.10 Effects of different concentrations of quercetin on ERK/p38 expression in the cardiomyocytes in each group. A, B: Effects of quercetin on expressions of ERK and p38 mRNA in the cells. C: Western blotting of p-ERK, ERK, p-p38 and p38 proteins. D, E: Expression of p-ERK/ERK and p-p38/p38 protein in the cells. ##P<0.01 vs Control group, *P<0.05, **P<0.01, ***P<0.001 vs ISO group (n=3).

Fig.11 Effects of different concentrations of quercetin on expressions of apoptosis-related proteins in cardiomyocytes treated with ERK/p38 pathway inhibitors. A: Effects of different concentrations of quercetin on the expression of Bax, Bcl-2 and caspase-3 in the cells after adding ERK inhibitor (TBHQ) and p38 inhibitor (SB 203580). B: Ratio of Bax/Bcl-2 protein expression. C: Ratio of cleaved-caspase-3/caspase-3 protein expression. ##P<0.01 vs Control group, **P<0.01 vs ISO group, △△P<0.01 vs ISO+Que group (n=3).

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