A Newly Synthesized Flavone Avoids COMT-catalyzed Methylation and Mitigates Myocardial Ischemia/reperfusion Injury in H9C2 Cells Via JNK and P38 Pathways

Overview

Journal Iran J Basic Med Sci

Publisher Mashhad University of Medical Sciences

Specialty General Medicine

Date 2024 Feb 29

PMID 38419895

Authors

Ye Lin

Xin Yang

Yan Li

De-Jian Huang

Zhi-Qin Sun

Affiliations

Soon will be listed here.

Abstract

Objectives: Luteolin is a flavone that provides defense against myocardial ischemia/reperfusion (I/R) injury. However, this compound is subjected to methylation mediated by catechol-O-methyltransferase (COMT), thus influencing its pharmacological effect. To synthesize a new flavone from luteolin that avoids COMT-catalyzed methylation and find out the protective mechanism of LUA in myocardial I/R injury.

Materials And Methods: Luteolin and 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) were used to synthesize the new flavone known as LUAAPH-1 (LUA). Then, the myocardial ischemia/reperfusion injury cell model was established using H9c2 cells to detect the effect in myocardial ischemia/reperfusion regulation and to identify the underlying mechanism.

Results: Pretreatment with LUA (20 μmol/l) substantially increased cell viability while reducing cell apoptosis rate and caspase-3 expression induced by I/R, and the protective effect of LUA on cell viability was stronger than diosmetin, which is the major methylated metabolite of luteolin. In addition, intracellular reactive oxygen species (ROS) production and calcium accumulation were both inhibited by LUA. Furthermore, we identified that LUA markedly relieved the promotive effects of I/R stimulation upon JNK and p38 phosphorylation.

Conclusion: LUT pretreatment conveys significant cardioprotective effects after myocardial I/R injury, and JNK and p38 MAPK signaling pathway may be involved.

Citing Articles

Magea13 attenuates myocardial injury in acute myocardial infarction by inhibiting the cAMP-PKA signaling pathway.

Zheng J, Xu X, Zhang Z, Ge K, Xiang Y, Dai H Apoptosis. 2025; .

PMID: 40056358 DOI: 10.1007/s10495-025-02078-0.

References

Li H, Xia Z, Chen Y, Qi D, Zheng H . Mechanism and Therapies of Oxidative Stress-Mediated Cell Death in Ischemia Reperfusion Injury. Oxid Med Cell Longev. 2018; 2018:2910643. PMC: 6035842. DOI: 10.1155/2018/2910643. View

Chen Y, Liu C, Zhou P, Li J, Zhao X, Wang Y . Coronary Endothelium No-Reflow Injury Is Associated with ROS-Modified Mitochondrial Fission through the JNK-Drp1 Signaling Pathway. Oxid Med Cell Longev. 2021; 2021:6699516. PMC: 7878075. DOI: 10.1155/2021/6699516. View

Gonzalez-Montero J, Brito R, Gajardo A, Rodrigo R . Myocardial reperfusion injury and oxidative stress: Therapeutic opportunities. World J Cardiol. 2018; 10(9):74-86. PMC: 6189069. DOI: 10.4330/wjc.v10.i9.74. View

Wang L, Chen Q, Zhu L, Li Q, Zeng X, Lu L . Metabolic Disposition of Luteolin Is Mediated by the Interplay of UDP-Glucuronosyltransferases and Catechol-O-Methyltransferases in Rats. Drug Metab Dispos. 2016; 45(3):306-315. PMC: 6041822. DOI: 10.1124/dmd.116.073619. View

Zhai M, Li B, Duan W, Jing L, Zhang B, Zhang M . Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis. J Pineal Res. 2017; 63(2). DOI: 10.1111/jpi.12419. View

Horvathova K, Novotny L, Tothova D, Vachalkova A . Determination of free radical scavenging activity of quercetin, rutin, luteolin and apigenin in H2O2-treated human ML cells K562. Neoplasma. 2005; 51(5):395-9. View

Ma L, Zou R, Shi W, Zhou N, Chen S, Zhou H . SGLT2 inhibitor dapagliflozin reduces endothelial dysfunction and microvascular damage during cardiac ischemia/reperfusion injury through normalizing the XO-SERCA2-CaMKII-coffilin pathways. Theranostics. 2022; 12(11):5034-5050. PMC: 9274739. DOI: 10.7150/thno.75121. View

Huang D, Ou B, Hampsch-Woodill M, Flanagan J, Prior R . High-throughput assay of oxygen radical absorbance capacity (ORAC) using a multichannel liquid handling system coupled with a microplate fluorescence reader in 96-well format. J Agric Food Chem. 2002; 50(16):4437-44. DOI: 10.1021/jf0201529. View

Pena E, Brito J, El Alam S, Siques P . Oxidative Stress, Kinase Activity and Inflammatory Implications in Right Ventricular Hypertrophy and Heart Failure under Hypobaric Hypoxia. Int J Mol Sci. 2020; 21(17). PMC: 7503689. DOI: 10.3390/ijms21176421. View

10.

Zhu H, Jin Q, Li Y, Ma Q, Wang J, Li D . Melatonin protected cardiac microvascular endothelial cells against oxidative stress injury via suppression of IP3R-[Ca]c/VDAC-[Ca]m axis by activation of MAPK/ERK signaling pathway. Cell Stress Chaperones. 2017; 23(1):101-113. PMC: 5741585. DOI: 10.1007/s12192-017-0827-4. View

11.

Chen Z, Dai Y, Kong S, Song F, Li L, Ye J . Luteolin is a rare substrate of human catechol-O-methyltransferase favoring a para-methylation. Mol Nutr Food Res. 2013; 57(5):877-85. DOI: 10.1002/mnfr.201200584. View

12.

Zhang R, Li D, Xu T, Zhu S, Pan H, Fang F . Antioxidative effect of luteolin pretreatment on simulated ischemia/reperfusion injury in cardiomyocyte and perfused rat heart. Chin J Integr Med. 2016; 23(7):518-527. DOI: 10.1007/s11655-015-2296-x. View

13.

Binu P, Soman R, Zakhariah Hisham O, Narayanan S, Harikumaran Nair R . Acute promyelocytic leukemia drug - arsenic trioxide in the presence of eugenol shows differential action on leukemia cells (HL-60) and cardiomyocytes (H9c2) - inference from NMR study. Toxicol Mech Methods. 2021; 31(6):457-466. DOI: 10.1080/15376516.2021.1913685. View

14.

Mei Z, Du L, Liu X, Chen X, Tian H, Deng Y . Diosmetin alleviated cerebral ischemia/reperfusion injury and by inhibiting oxidative stress the SIRT1/Nrf2 signaling pathway. Food Funct. 2021; 13(1):198-212. DOI: 10.1039/d1fo02579a. View

15.

Zhang C, Cheng Y, Liu D, Liu M, Cui H, Zhang B . Mitochondria-targeted cyclosporin A delivery system to treat myocardial ischemia reperfusion injury of rats. J Nanobiotechnology. 2019; 17(1):18. PMC: 6346555. DOI: 10.1186/s12951-019-0451-9. View

16.

Chen Z, Tu M, Sun S, Kong S, Wang Y, Ye J . The exposure of luteolin is much lower than that of apigenin in oral administration of Flos Chrysanthemi extract to rats. Drug Metab Pharmacokinet. 2011; 27(1):162-8. DOI: 10.2133/dmpk.dmpk-11-rg-081. View

17.

Du Y, Liu P, Xu T, Pan D, Zhu H, Zhai N . Luteolin Modulates SERCA2a Leading to Attenuation of Myocardial Ischemia/ Reperfusion Injury via Sumoylation at Lysine 585 in Mice. Cell Physiol Biochem. 2018; 45(3):883-898. DOI: 10.1159/000487283. View

18.

Ye L, Xin Y, Wu Z, Sun H, Huang D, Sun Z . A Newly Synthesized Flavone from Luteolin Escapes from COMT-Catalyzed Methylation and Inhibits Lipopolysaccharide-Induced Inflammation in RAW264.7 Macrophages via JNK, p38 and NF-κB Signaling Pathways. J Microbiol Biotechnol. 2021; 32(1):15-26. PMC: 9628824. DOI: 10.4014/jmb.2104.04027. View

19.

Wei B, Lin Q, Ji Y, Zhao Y, Ding L, Zhou W . Luteolin ameliorates rat myocardial ischaemia-reperfusion injury through activation of peroxiredoxin II. Br J Pharmacol. 2018; 175(16):3315-3332. PMC: 6057904. DOI: 10.1111/bph.14367. View

20.

Zhu S, Xu T, Luo Y, Zhang Y, Xuan H, Ma Y . Luteolin Enhances Sarcoplasmic Reticulum Ca2+-ATPase Activity through p38 MAPK Signaling thus Improving Rat Cardiac Function after Ischemia/Reperfusion. Cell Physiol Biochem. 2017; 41(3):999-1010. DOI: 10.1159/000460837. View