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).

References 36

1	Baman JR, Ahmad FS. Heart failure[J]. JAMA, 2020, 324(10): 1015.
2	射血分数保留的心力衰竭诊断与治疗中国专家共识制定工作组. 射血分数保留的心力衰竭诊断与治疗中国专家共识2023[J]. 中国循环杂志, 2023, 38(4): 375-93.
3	McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure[J]. Eur Heart J, 2021, 42(36): 3599-726.
4	Mascolo A, di Mauro G, Cappetta D, et al. Current and future therapeutic perspective in chronic heart failure[J]. Pharmacol Res, 2022, 175: 106035.
5	Bai BB, Ji ZL, Wang FF, et al. CTRP12 ameliorates post-myocardial infarction heart failure through down-regulation of cardiac apo-ptosis, oxidative stress and inflammation by influencing the TAK1-p38 MAPK/JNK pathway[J]. Inflamm Res, 2023, 72(7): 1375-90.
6	Zhang SY, Liu HB, Fang QQ, et al. Shexiang Tongxin dropping pill protects against chronic heart failure in mice via inhibiting the ERK/MAPK and TGF‑β signaling pathways[J]. Front Pharmacol, 2021, 12: 796354.
7	Wan CR, Han DD, Xu JQ, et al. Jujuboside A attenuates norepinephrine-induced apoptosis of H9c2 cardiomyocytes by modulating MAPK and AKT signaling pathways[J]. Mol Med Rep, 2018, 17(1): 1132-40.
8	Hu QC, Qu CY, Xiao XL, et al. Flavonoids on diabetic nephropathy: advances and therapeutic opportunities[J]. Chin Med, 2021, 16(1): 74.
9	Zhang WW, Zheng Y, Yan F, et al. Research progress of quercetin in cardiovascular disease[J]. Front Cardiovasc Med, 2023, 10: 1203713.
10	Wang SH, Tsai KL, Chou WC, et al. Quercetin mitigates cisplatin-induced oxidative damage and apoptosis in cardiomyocytes through Nrf2/HO-1 signaling pathway[J]. Am J Chin Med, 2022, 50(5): 1281-98.
11	李霞, 程贝贝, 谭骏岚, 等. 黄芪主成分槲皮素通过MAPK通路调控PASMCs铁死亡抗低氧性肺动脉高压的研究(英文)[J]. 中国药学(英文版), 2024, 33(8): 714-29.
12	谭鑫, 鲜维, 陈永锋, 等. 槲皮素治疗心力衰竭的分子机制：基于网络药理学与分子对接方法[J]. 南方医科大学学报, 2021, 41(8): 1198-206.
13	Nogales C, Mamdouh ZM, List M, et al. Network pharmacology: curing causal mechanisms instead of treating symptoms[J]. Trends Pharmacol Sci, 2022, 43(2): 136-50.
14	Shi TT, Hou CQ, Duan YZ, et al. Mechanism of Smilax China L. in the treatment of intrauterine adhesions based on network pharmacology, molecular docking and experimental validation[J]. BMC Complement Med Ther, 2024, 24(1): 150.
15	Li X, Wei SZ, Niu SQ, et al. Network pharmacology prediction and molecular docking-based strategy to explore the potential mechanism of Huanglian Jiedu Decoction against sepsis[J]. Comput Biol Med, 2022, 144: 105389.
16	Sauer AJ, Cole R, Jensen BC, et al. Practical guidance on the use of sacubitril/valsartan for heart failure[J]. Heart Fail Rev, 2019, 24(2): 167-76.
17	Hyman DA, Siebert VR, Birnbaum GD, et al. A modern history RAAS inhibition and beta blockade for heart failure to underscore the non-equivalency of ACEIs and ARBs[J]. Cardiovasc Drugs Ther, 2020, 34(2): 215-21.
18	Romero-Becerra R, Santamans AM, Folgueira C, et al. p38 MAPK pathway in the heart: new insights in health and disease[J]. Int J Mol Sci, 2020, 21(19): 7412.
19	Zhang M, Li YC, Wang YQ, et al. Quercetin inhibition of myocardial fibrosis through regulating MAPK signaling pathway via ROS[J]. Pak J Pharm Sci, 2019, 32(3 Special): 1355-9.
20	Tan X, Xian W, Li XR, et al. Mechanisms of Quercetin against atrial fibrillation explored by network pharmacology combined with molecular docking and experimental validation[J]. Sci Rep, 2022, 12(1): 9777.
21	Bass-Stringer S, Tai CMK, McMullen JR. IGF1-PI3K-induced physiological cardiac hypertrophy: implications for new heart failure therapies, biomarkers, and predicting cardiotoxicity[J]. J Sport Health Sci, 2021, 10(6): 637-47.
22	Gao JY, Feng WJ, Lv W, et al. HIF-1/AKT signaling-activated PFKFB2 alleviates cardiac dysfunction and cardiomyocyte apoptosis in response to hypoxia[J]. Int Heart J, 2021, 62(2): 350-8.
23	Al-Rasheed NM, Fadda LM, Attia HA, et al. Quercetin inhibits sodium nitrite-induced inflammation and apoptosis in different rats organs by suppressing Ba _x, HIF1‑α, TGF‑β, Smad-2, and AKT pathways[J]. J Biochem Mol Toxicol, 2017, 31(5). doi: 10.1002/jbt.21883 .
24	Fang Z, Yushanjiang F, Wang GJ, et al. Germacrone mitigates cardiac remodeling by regulating PI3K/AKT-mediated oxidative stress, inflammation, and apoptosis[J]. Int Immunopharmacol, 2023, 124(Pt A): 110876.
25	Fu C, Yao YYY, Li LB, et al. P4239Bradykinin inhibits High Glucose-Induced Senescence of c-kit Positive Cardiac Stem Cells via B2R/PI3K/AKT/mTOR/P53 signal pathway[J]. Eur Heart J, 2017, 38(): ehx504.P4239.
26	Tang XY, Jiang HL, Lin PY, et al. Insulin-like growth factor binding protein-1 regulates HIF-1α degradation to inhibit apoptosis in hypoxic cardiomyocytes[J]. Cell Death Discov, 2021, 7(1): 242.
27	Wang L, Wu HW, Xiong L, et al. Quercetin downregulates cyclooxygenase-2 expression and HIF-1α/VEGF signaling-related angiogenesis in a mouse model of abdominal aortic aneurysm[J]. Biomed Res Int, 2020, 2020: 9485398.
28	Meijles DN, Cull JJ, Markou T, et al. Redox regulation of cardiac ASK1 (apoptosis signal-regulating kinase 1) controls p38-MAPK (mitogen-activated protein kinase) and orchestrates cardiac remodeling to hypertension[J]. Hypertension, 2020, 76(4): 1208-18.
29	Cheng J, Huang Y, Zhang XH, et al. TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism[J]. Nat Commun, 2020, 11(1): 1880.
30	Moulin S, Thomas A, Wagner S, et al. Intermittent hypoxia-induced cardiomyocyte death is mediated by HIF-1 dependent MAM disruption[J]. Antioxidants, 2022, 11(8): 1462.
31	Fleisher TA. Apoptosis[J]. Ann Allergy Asthma Immunol, 1997, 78(3): 245-50.
32	Lin XY, Ouyang SY, Zhi CX, et al. Focus on ferroptosis, pyroptosis, apoptosis and autophagy of vascular endothelial cells to the strategic targets for the treatment of atherosclerosis[J]. Arch Biochem Biophys, 2022, 715: 109098.
33	Liu YL, Yang LQ, Yin JM, et al. MicroRNA-15b deteriorates hypoxia/reoxygenation-induced cardiomyocyte apoptosis by down-regulating bcl-2 and MAPK3[J]. J Investig Med, 2018, 66(1): 39-45.
34	Chen SN, Lombardi R, Karmouch J, et al. DNA damage response/TP53 pathway is activated and contributes to the pathogenesis of dilated cardiomyopathy associated with LMNA (lamin A/C) mutations[J]. Circ Res, 2019, 124(6): 856-73.
35	Chen YF, Qiu Q, Wang L, et al. Quercetin ameliorates myocardial injury in diabetic rats by regulating autophagy and apoptosis through AMPK/mTOR signaling pathway[J]. Am J Chin Med, 2024, 52(3): 841-64.
36	de Lacerda Alexandre JV, Viana YIP, David CEB, et al. Quercetin treatment increases H₂O₂ removal by restoration of endogenous antioxidant activity and blocks isoproterenol-induced cardiac hypertrophy[J]. Naunyn Schmiedebergs Arch Pharmacol, 2021, 394(2): 217-26.

[1]	Xinyuan CHEN, Chengting WU, Ruidi LI, Xueqin PAN, Yaodan ZHANG, Junyu TAO, Caizhi LIN. Shuangshu Decoction inhibits growth of gastric cancer cell xenografts by promoting cell ferroptosis via the P53/SLC7A11/GPX4 axis [J]. Journal of Southern Medical University, 2025, 45(7): 1363-1371.
[2]	Liming WANG, Hongrui CHEN, Yan DU, Peng ZHAO, Yujie WANG, Yange TIAN, Xinguang LIU, Jiansheng LI. Yiqi Zishen Formula ameliorates inflammation in mice with chronic obstructive pulmonary disease by inhibiting the PI3K/Akt/NF-κB signaling pathway [J]. Journal of Southern Medical University, 2025, 45(7): 1409-1422.
[3]	Yinfu ZHU, Yiran LI, Yi WANG, Yinger HUANG, Kunxiang GONG, Wenbo HAO, Lingling SUN. Therapeutic mechanism of hederagenin, an active component in Guizhi Fuling Pellets, against cervical cancer in nude mice [J]. Journal of Southern Medical University, 2025, 45(7): 1423-1433.
[4]	Lijun HE, Xiaofei CHEN, Chenxin YAN, Lin SHI. Inhibitory effect of Fuzheng Huaji Decoction against non-small cell lung cancer cells in vitro and the possible molecular mechanism [J]. Journal of Southern Medical University, 2025, 45(6): 1143-1152.
[5]	Guoyong LI, Renling LI, Yiting LIU, Hongxia KE, Jing LI, Xinhua WANG. Therapeutic mechanism of Arctium lappa extract for post-viral pneumonia pulmonary fibrosis: a metabolomics, network pharmacology analysis and experimental verification [J]. Journal of Southern Medical University, 2025, 45(6): 1185-1199.
[6]	Liping GUAN, Yan YAN, Xinyi LU, Zhifeng LI, Hui GAO, Dong CAO, Chenxi HOU, Jingyu ZENG, Xinyi LI, Yang ZHAO, Junjie WANG, Huilong FANG. Compound Centella asiatica formula alleviates Schistosoma japonicum-induced liver fibrosis in mice by inhibiting the inflammation-fibrosis cascade via regulating the TLR4/MyD88 pathway [J]. Journal of Southern Medical University, 2025, 45(6): 1307-1316.
[7]	Peipei TANG, Yong TAN, Yanyun YIN, Xiaowei NIE, Jingyu HUANG, Wenting ZUO, Yuling LI. Tiaozhou Ziyin recipe for treatment of premature ovarian insufficiency: efficacy, safety and mechanism [J]. Journal of Southern Medical University, 2025, 45(5): 929-941.
[8]	Xiaotao LIANG, Yifan XIONG, Xueqi LIU, Xiaoshan LIANG, Xiaoyu ZHU, Wei XIE. Huoxue Shufeng Granule alleviates central sensitization in chronic migraine mice via TLR4/NF-κB inflammatory pathway [J]. Journal of Southern Medical University, 2025, 45(5): 986-994.
[9]	Niandong RAN, Jie LIU, Jian XU, Yongping ZHANG, Jiangtao GUO. n-butanol fraction of ethanol extract of Periploca forrestii Schltr.: its active components, targets and pathways for treating Alcheimer's disease in rats [J]. Journal of Southern Medical University, 2025, 45(4): 785-798.
[10]	Hongyan SUN, Guoqing LU, Chengwen FU, Mengwen XU, Xiaoyi ZHU, Guoquan XING, Leqiang LIU, Yufei KE, Lemei CUI, Ruiyang CHEN, Lei WANG, Pinfang KANG, Bi TANG. Quercetin ameliorates myocardial injury in diabetic rats by regulating L-type calcium channels [J]. Journal of Southern Medical University, 2025, 45(3): 531-541.
[11]	Lixia YIN, Minzhu NIU, Keni ZHANG, Zhijun GENG, Jianguo HU, Jiangyan LI, Jing LI. Cimifugin ameliorates Crohn's disease-like colitis in mice by modulating Th-cell immune balance via inhibiting the MAPK pathway [J]. Journal of Southern Medical University, 2025, 45(3): 595-602.
[12]	Haonan¹ XU, Fang³ ZHANG, Yuying² HUANG, Qisheng⁴ YAO, Yueqin⁴ GUAN, Hao CHEN. Thesium chinense Turcz. alleviates antibiotic-associated diarrhea in mice by modulating gut microbiota structure and regulating the EGFR/PI3K/Akt signaling pathway [J]. Journal of Southern Medical University, 2025, 45(2): 285-295.
[13]	Pengwei HUANG, Jie CHEN, Jinhu ZOU, Xuefeng GAO, Hong CAO. Quercetin mitigates HIV-1 gp120-induced rat astrocyte neurotoxicity via promoting G3BP1 disassembly in stress granules [J]. Journal of Southern Medical University, 2025, 45(2): 304-312.
[14]	Junjie GAO, Kai YE, Jing WU. Quercetin inhibits proliferation and migration of clear cell renal cell carcinoma cells by regulating TP53 gene [J]. Journal of Southern Medical University, 2025, 45(2): 313-321.
[15]	Ying LIU, Borui LI, Yongcai LI, Lubo CHANG, Jiao WANG, Lin YANG, Yonggang YAN, Kai QV, Jiping LIU, Gang ZHANG, Xia SHEN. Jiawei Xiaoyao Pills improves depression-like behavior in rats by regulating neurotransmitters, inhibiting inflammation and oxidation and modulating intestinal flora [J]. Journal of Southern Medical University, 2025, 45(2): 347-358.