Dan Hong Injection Protects Against Cardiomyocytes Apoptosis by Maintaining Mitochondrial Integrity Through Keap1/Nuclear Factor Erythroid 2-Related Factor 2/JNK Pathway

Overview

Journal Front Pharmacol

Date 2020 Dec 16

PMID 33324219

Citations 6

Authors

Ling Zhang

Yu Wang

Chang Li

Chongyu Shao

Huifen Zhou

Jiehong Yang

Yu He

Haitong Wan

Affiliations

Soon will be listed here.

Abstract

Danhong injection (DHI) is used widely against cardiovascular disease in China. Recent studies have demonstrated its mitochondria-protection effect as being pivotal in treatment of myocardial ischemia/reperfusion (I/R) injury, but the underlying mechanism of action is incompletely understood. We aimed to identify the effect and mechanism of action of DHI on mitochondrial integrity and cardiomyocyte apoptosis after I/R. An I/R rat model was induced to detect the effect of DHI on myocardial repair by infarct size, apoptosis and oxidative stress. , H9C2 cells or H9C2 cells with nuclear factor erythroid 2-related factor 2 (Nrf2) knockdown were injured under hypoxia-reoxygenation (H/R). The effects of DHI on apoptosis, antioxidant capacity and mitochondrial integrity were evaluated by mitochondrial morphology, apoptosis rate, reactive oxygen species (ROS) generation, ATP levels, mitochondrial membrane potential, and oxygen consumption in H9C2 cells treated with H/R. The underlying mechanism of action of DHI in maintenance of mitochondrial integrity and anti-apoptosis was detected in H9C2 cells with or without Nrf2 knockdown. DHI treatment significantly decreased the infarct size, inhibited apoptosis and suppressed oxidative stress in the hearts of I/R rats. Also, DHI promoted cell survival by: an anti-apoptosis action; inhibiting ROS generation; maintaining mitochondrial morphology with increased mitochondrial length; alleviating mitochondrial dysfunction with a decreased mitochondrial membrane potential; increasing ATP levels and the oxygen-consumption rate. Moreover, the Keap1/Nrf2/JNK pathway was found to be involved in DHI reducing oxidative stress and maintaining mitochondrial integrity. We revealed a novel mechanism by which DHI protected H9C2 cells against H/R injury the Keap1/Nrf2/JNK pathway and provided a mitochondrial protectant for the treatment of myocardial I/R injury.

Citing Articles

Mitochondria-Associated Organelle Crosstalk in Myocardial Ischemia/Reperfusion Injury.

Yao H, Xie Y, Li C, Liu W, Yi G J Cardiovasc Transl Res. 2024; 17(5):1106-1118.

PMID: 38807004 DOI: 10.1007/s12265-024-10523-9.

Galangin Attenuates Myocardial Ischemic Reperfusion-Induced Ferroptosis by Targeting Nrf2/Gpx4 Signaling Pathway.

Yang T, Liu H, Yang C, Mo H, Wang X, Song X Drug Des Devel Ther. 2023; 17:2495-2511.

PMID: 37637264 PMC: 10460190. DOI: 10.2147/DDDT.S409232.

Chinese herbal injection for cardio-cerebrovascular disease: Overview and challenges.

Huajuan J, Xulong H, Bin X, Yue W, Yongfeng Z, Chaoxiang R Front Pharmacol. 2023; 14:1038906.

PMID: 36909150 PMC: 9998719. DOI: 10.3389/fphar.2023.1038906.

Neuroprotective Effect of miR-483-5p Against Cardiac Arrest-Induced Mitochondrial Dysfunction Mediated Through the TNFSF8/AMPK/JNK Signaling Pathway.

Zhang Q, Zhan H, Liu C, Zhang C, Wei H, Li B Cell Mol Neurobiol. 2022; 43(5):2179-2202.

PMID: 36266523 PMC: 10287582. DOI: 10.1007/s10571-022-01296-3.

Detection of an anti-angina therapeutic module in the effective population treated by a multi-target drug Danhong injection: a randomized trial.

Li D, Dong W, Liu Y, Wu Y, Tang D, Zhang F Signal Transduct Target Ther. 2021; 6(1):329.

PMID: 34471087 PMC: 8410855. DOI: 10.1038/s41392-021-00741-x.

References

Li Q, Xiang Y, Chen Y, Tang Y, Zhang Y . Ginsenoside Rg1 Protects Cardiomyocytes Against Hypoxia/Reoxygenation Injury via Activation of Nrf2/HO-1 Signaling and Inhibition of JNK. Cell Physiol Biochem. 2017; 44(1):21-37. DOI: 10.1159/000484578. View

Ibanez B, Heusch G, Ovize M, Van de Werf F . Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol. 2015; 65(14):1454-71. DOI: 10.1016/j.jacc.2015.02.032. View

Liu Y, Tao S, Liao L, Li Y, Li H, Li Z . TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway. Nat Commun. 2020; 11(1):348. PMC: 6969153. DOI: 10.1038/s41467-019-14190-2. View

Ma X, Yin S, Jin J, Wu C, Huang Y, Shi D . Synergistic protection of Danhong injection (丹红注射液) and ischemic postconditioning on myocardial reperfusion injury in minipigs. Chin J Integr Med. 2010; 16(6):531-6. DOI: 10.1007/s11655-010-0567-0. View

Wallace D . Mitochondrial diseases in man and mouse. Science. 1999; 283(5407):1482-8. DOI: 10.1126/science.283.5407.1482. View

Wallace D . A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005; 39:359-407. PMC: 2821041. DOI: 10.1146/annurev.genet.39.110304.095751. View

Su X, Yang W, Zhi X . Effect of danhong injection on expressions of macrophage scavenger receptor 1 and sub-family A member 1 in human U937 cells. J Tradit Chin Med. 2013; 33(3):384-7. DOI: 10.1016/s0254-6272(13)60183-1. View

Liu C, Huang Y . Chinese Herbal Medicine on Cardiovascular Diseases and the Mechanisms of Action. Front Pharmacol. 2016; 7:469. PMC: 5130975. DOI: 10.3389/fphar.2016.00469. View

Guo X, Aviles G, Liu Y, Tian R, Unger B, Lin Y . Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway. Nature. 2020; 579(7799):427-432. PMC: 7147832. DOI: 10.1038/s41586-020-2078-2. View

10.

Tait S, Green D . Mitochondria and cell signalling. J Cell Sci. 2012; 125(Pt 4):807-15. PMC: 3311926. DOI: 10.1242/jcs.099234. View

11.

Ding S, Yang Y, Mei J . Protective Effects of L-Malate against Myocardial Ischemia/Reperfusion Injury in Rats. Evid Based Complement Alternat Med. 2016; 2016:3803657. PMC: 4752987. DOI: 10.1155/2016/3803657. View

12.

You Q, Wang J, Dong W, Tian F, Liu H, Jing J . Protective effect of injection in patients with acute myocardial infarction at a high risk of no-reflow during primary percutaneous coronary intervention. J Geriatr Cardiol. 2019; 16(5):406-413. PMC: 6558573. DOI: 10.11909/j.issn.1671-5411.2019.05.001. View

13.

Lyu M, Yan C, Liu H, Wang T, Shi X, Liu J . Network pharmacology exploration reveals endothelial inflammation as a common mechanism for stroke and coronary artery disease treatment of Danhong injection. Sci Rep. 2017; 7(1):15427. PMC: 5684234. DOI: 10.1038/s41598-017-14692-3. View

14.

Cadenas S . ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection. Free Radic Biol Med. 2018; 117:76-89. DOI: 10.1016/j.freeradbiomed.2018.01.024. View

15.

Song Z, Zhang Y, Zhang H, Rajendran R, Wang R, Hsiao C . Isoliquiritigenin triggers developmental toxicity and oxidative stress-mediated apoptosis in zebrafish embryos/larvae via Nrf2-HO1/JNK-ERK/mitochondrion pathway. Chemosphere. 2020; 246:125727. DOI: 10.1016/j.chemosphere.2019.125727. View

16.

Chen J, Wei J, Orgah J, Zhu Y, Ni J, Li L . Cardioprotective Effect of Danhong Injection against Myocardial Infarction in Rats Is Critically Contributed by MicroRNAs. Evid Based Complement Alternat Med. 2019; 2019:4538985. PMC: 6732666. DOI: 10.1155/2019/4538985. View

17.

Rabinovich-Nikitin I, Lieberman B, Martino T, Kirshenbaum L . Circadian-Regulated Cell Death in Cardiovascular Diseases. Circulation. 2019; 139(7):965-980. DOI: 10.1161/CIRCULATIONAHA.118.036550. View

18.

Barth E, Stammler G, Speiser B, Schaper J . Ultrastructural quantitation of mitochondria and myofilaments in cardiac muscle from 10 different animal species including man. J Mol Cell Cardiol. 1992; 24(7):669-81. DOI: 10.1016/0022-2828(92)93381-s. View

19.

Bae S, Sung S, Oh S, Lim J, Lee S, Park Y . Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. Cell Metab. 2013; 17(1):73-84. DOI: 10.1016/j.cmet.2012.12.002. View

20.

Pell V, Chouchani E, Murphy M, Brookes P, Krieg T . Moving Forwards by Blocking Back-Flow: The Yin and Yang of MI Therapy. Circ Res. 2016; 118(5):898-906. PMC: 4809200. DOI: 10.1161/CIRCRESAHA.115.306569. View