Matrine attenuates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity  via  maintaining AMPK α /UCP2 pathway

Author(s): Can Hu ^a ^, ^b ^, ^c ^, ^† , Xin Zhang ^a ^, ^b ^, ^c ^, ^† , Wenying Wei ^a ^, ^b ^, ^c , Ning Zhang ^a ^, ^b ^, ^c , Haiming Wu ^a ^, ^b ^, ^c , Zhenguo Ma ^a ^, ^b ^, ^c , Lingli Li ^a ^, ^b ^, ^c , Wei Deng ^a ^, ^b ^, ^c ^, ^* , Qizhu Tang ^a ^, ^b ^, ^c ^, ^*

Publication date (Electronic): 16 March 2019

Journal: Acta Pharmaceutica Sinica. B

Publisher: Elsevier

Keywords: 4-HNE, 4-hydroxynonenal, ACC, acetyl-CoA carboxylase, AMPKα, 5′-AMP-activated protein kinase α, ANOVA, analysis of variance, BAX, BCL-2-associated X protein, BCL-2, B-cell lymphoma 2, C-caspase 3, cleaved-caspase3, CCK-8, cell counting kit 8, CK-MB, creatine kinase isoenzymes, cTnT, cardiac isoform of Tropnin T, DCFH-DA, 2′,7′-dichlorodihydrofluorescein diacetate, DHE, dihydroethidium, DMEM, Dulbecco׳s modified Eagle׳s medium, DOX, doxorubicin, FBS, fetal bovine serum, FS, fractional shortening, GAPDH, glyceraldehyde 3-phosphate dehydrogenase, HW, heart weight, LDH, lactate dehydrogenase, MDA, malondialdehyde, BCA, bicinchoninic acid, PPARs, peroxisomal proliferators-activated receptors, ROS, reactive oxygen species, SOD2, superoxide dismutase 2, T-caspase3, total-caspase3, TL, tibia length, Top2, topoisomerase-II, TUNEL, TdT-mediated dUTP nick end-labelling, UCP2, uncoupling protein 2, Matrine, Oxidative stress, Apoptosis, AMPKα, UCP2

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Abstract

Oxidative stress and cardiomyocyte apoptosis are involved in the pathogenesis of doxorubicin (DOX)-induced cardiotoxicity. Matrine is well-known for its powerful anti-oxidant and anti-apoptotic capacities. Our present study aimed to investigate the effect of matrine on DOX-induced cardiotoxicity and try to unearth the underlying mechanisms. Mice were exposed with DOX to generate DOX-induced cardiotoxicity or normal saline as control. H9C2 cells were used to verify the effect of matrine in vitro. DOX injection triggered increased generation of reactive oxygen species (ROS) and excessive cardiomyocyte apoptosis, which were significantly mitigated by matrine. Mechanistically, we found that matrine ameliorated DOX-induced uncoupling protein 2 (UCP2) downregulation, and UCP2 inhibition by genipin could blunt the protective effect of matrine on DOX-induced oxidative stress and cardiomyocyte apoptosis. Besides, 5′-AMP-activated protein kinase α2 ( Ampkα2) deficiency inhibited matrine-mediated UCP2 preservation and abolished the beneficial effect of matrine in mice. Besides, we observed that matrine incubation alleviated DOX-induced H9C2 cells apoptosis and oxidative stress level via activating AMPK α/UCP2, which were blunted by either AMPK α or UCP2 inhibition with genetic or pharmacological methods. Matrine attenuated oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity via maintaining AMPK α/UCP2 pathway, and it might be a promising therapeutic agent for the treatment of DOX-induced cardiotoxicity.

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Matrine attenuated oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity via maintaining AMPK α/UCP2 pathway, and it might be a promising therapeutic agent for the treatment of DOX-induced cardiotoxicity.

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Most cited references 47

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Superoxide flashes in single mitochondria.

Wang Wang, Huaqiang Fang, Linda Groom … (2008)

In quiescent cells, mitochondria are the primary source of reactive oxygen species (ROS), which are generated by leakiness of the electron transport chain (ETC). High levels of ROS can trigger cell death, whereas lower levels drive diverse and important cellular functions. We show here by employing a newly developed mitochondrial matrix-targeted superoxide indicator, that individual mitochondria undergo spontaneous bursts of superoxide generation, termed "superoxide flashes." Superoxide flashes occur randomly in space and time, exhibit all-or-none properties, and provide a vital source of superoxide production across many different cell types. Individual flashes are triggered by transient openings of the mitochondrial permeability transition pore stimulating superoxide production by the ETC. Furthermore, we observe a flurry of superoxide flash activity during reoxygenation of cardiomyocytes after hypoxia, which is inhibited by the cardioprotective compound adenosine. We propose that superoxide flashes could serve as a valuable biomarker for a wide variety of oxidative stress-related diseases.

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Irisin protects mitochondria function during pulmonary ischemia/reperfusion injury

Yonggang Yao, Chunyu Zeng, Jianjie Ma … (2017)

Limb remote ischemic preconditioning (RIPC) is an effective means of protection against ischemia/reperfusion (IR)–induced injury to multiple organs. Many studies are focused on identifying endocrine mechanisms that underlie the cross-talk between muscle and RIPC-mediated organ protection. We report that RIPC releases irisin, a myokine derived from the extracellular portion of fibronectin domain–containing 5 protein (FNDC5) in skeletal muscle, to protect against injury to the lung. Human patients with neonatal respiratory distress syndrome show reduced concentrations of irisin in the serum and increased irisin concentrations in the bronchoalveolar lavage fluid, suggesting transfer of irisin from circulation to the lung under physiologic stress. In mice, application of brief periods of ischemia preconditioning stimulates release of irisin into circulation and transfer of irisin to the lung subjected to IR injury. Irisin, via lipid raft–mediated endocytosis, enters alveolar cells and targets mitochondria. Interaction between irisin and mitochondrial uncoupling protein 2 (UCP2) allows for prevention of IR-induced oxidative stress and preservation of mitochondrial function. Animal model studies show that intravenous administration of exogenous irisin protects against IR-induced injury to the lung via improvement of mitochondrial function, whereas in UCP2-deficient mice or in the presence of a UCP2 inhibitor, the protective effect of irisin is compromised. These results demonstrate that irisin is a myokine that facilitates RIPC-mediated lung protection. Targeting the action of irisin in mitochondria presents a potential therapeutic intervention for pulmonary IR injury.

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Is Open Access

Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: current strategies and future perspectives

Gantumur Battogtokh, Yeon Choi, Dong Seop Kang … (2018)

Mitochondrial targeting is a promising approach for solving current issues in clinical application of chemotherapy and diagnosis of several disorders. Here, we discuss direct conjugation of mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. Among them, the most widely applied mitochondrial targeting moiety is triphenylphosphonium (TPP), which is a delocalized cationic lipid that readily accumulates and penetrates through the mitochondrial membrane due to the highly negative mitochondrial membrane potential. Other moieties, including short peptides, dequalinium, guanidine, rhodamine, and F16, are also known to be promising mitochondrial targeting agents. Direct conjugation of mitochondrial targeting moieties to anticancer drugs, antioxidants and sensors results in increased cytotoxicity, anti-oxidizing activity and sensing activity, respectively, compared with their non-targeting counterparts, especially in drug-resistant cells. Although many mitochondria-targeted anticancer drug conjugates have been investigated in vitro and in vivo, further clinical studies are still needed. On the other hand, several mitochondria-targeting antioxidants have been analyzed in clinical phases I, II and III trials, and one conjugate has been approved for treating eye disease in Russia. There are numerous ongoing studies of mitochondria-targeted sensors.

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Author and article information

Contributors

Wei Deng

Qizhu Tang

Journal

Journal ID (nlm-ta): Acta Pharm Sin B

Journal ID (iso-abbrev): Acta Pharm Sin B

Title: Acta Pharmaceutica Sinica. B

Publisher: Elsevier

ISSN (Print): 2211-3835

ISSN (Electronic): 2211-3843

Publication date PMC-release: 16 March 2019

Publication date (Print): July 2019

Publication date (Electronic): 16 March 2019

Volume: 9

Issue: 4

Pages: 690-701

Affiliations

[a ]Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China

[b ]Cardiovascular Research Institute of Wuhan University, Wuhan 430060, China

[c ]Hubei Key Laboratory of Cardiology, Wuhan 430060, China

Author notes

[* ]Corresponding authors. Tel.: +86 27 88073385; fax: +86 27 88042292. vivideng1982@ 123456whu.edu.cn qztang@ 123456whu.edu.cn

[†]

These authors made equal contributions to this work.

Article

Publisher ID: S2211-3835(18)31151-1

DOI: 10.1016/j.apsb.2019.03.003

PMC ID: 6664099

PubMed ID: 31384530

SO-VID: 234c353f-9bba-41c2-a486-65892e331cf2

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Matrine attenuates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via maintaining AMPK α/UCP2 pathway

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Most cited references 47

Superoxide flashes in single mitochondria.

Irisin protects mitochondria function during pulmonary ischemia/reperfusion injury

Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: current strategies and future perspectives

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