2025年5月30日 周五
Home > Archive>Volume 32, Issue 6, 2024 >473-480. DOI:10.20039/j.cnki.10073949.2024.06.003.
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Effect of the mitochondrial H2S donor AP39 on myocardial fibrosis in rats with myocardial infarction and its relationship to mitochondrial dynamics
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Affiliation:

1.School of Pharmaceutical Science, University of South China, Hengyang, Hunan 421000, China;2.Department of Pharmacy, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421000, China;3.Department of Cardiology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421000, China)

Clc Number:

R966；R5

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    Abstract:

    Aim Previous studies have indicated that H2S can attenuate myocardial fibrosis. However, it is unclear whether mitochondria-targeted H2S can attenuate myocardial fibrosis after myocardial infarction and whether its mechanism is associated with the regulation of mitochondrial fusion and fission. To investigate this relationship, this study was conducted. Methods Isoproterenol (ISO, 50 mg/(kg·d) was injected intraperitoneally to induce myocardial infarction in SD rats. Electrocardiograms were performed on each group of rats, and the rats were treated with AP39 (36 μg/(kg·d), intraperitoneal) for 4 weeks. Masson's staining was used to assess the extent of myocardial fibrosis. Western blot was used to measure the expression of relevant proteins. In vitro experiments were performed to induce hypoxic injury in H9c2 cardiomyocytes with CoCl2 (800 μmol/L), H9c2 cells were treated with AP39 (100 nmol/L), and the endogenous hydrogen sulfide synthase cystathionine-γ-lyase(CSE) was inhibited using DL-propargylglycine (PAG, 2 mmol/L), and fluorescence probe was used to measure the level of reactive oxygen species(ROS) in myocardial cells. Results Myocardial fibrosis was evident in infarcted rat hearts, with a significant accumulation of collagen fibers. Additionally, the expression of CSE and mitofusin 2 (MFN2) proteins was downregulated, while dynamin-related protein 1(DRP1) protein expression was increased. Intervention with AP39 significantly improved the above changes, and the addition of CSE inhibitor PAG reversed the effects of AP39. In in vitro experiments, when H9c2 myocardial cells were subjected to hypoxic injury induced by CoCl2, intracellular ROS levels increased, MFN2 expression was downregulated, and DRP1 expression was upregulated. AP39 upregulated MFN2 protein expression, inhibited DRP1 protein expression, and reduced ROS levels in myocardial cells. The addition of PAG reversed these changes. Conclusion The mitochondria-targeted H2S donor, AP39, can improve myocardial fibrosis in rats with myocardial infarction and promote mitochondrial fusion and inhibit excessive mitochondrial division.

    Reference
    [1] 邱羽菲, 史嘉翊, 宋旭东, 等.心肌纤维化的发生机制及治疗研究进展.心脏杂志, 1,3(5):553-557.QIU Y F, SHI J Y, SONG X D, et al.Research progress in mechanism and treatment of myocardial fibrosis.Chin Heart J, 1,3(5):553-557.
    [2] LI Y Z, LIU X H.Novel insights into the role of mitochondrial fusion and fission in cardiomyocyte apoptosis induced by ischemia/reperfusion.J Cell Physiol, 8,3(8):5589-5597.
    [3] CASTAO C, MIRASIERRA M, VALLEJO M, et al.Delivery of muscle-derived exosomal miRNAs induced by HIIT improves insulin sensitivity through down-regulation of hepatic FoxO1 in mice.Proc Natl Acad Sci U S A, 0,7(48):30335-30343.
    [4] SHI R Y, ZHU S H, LI V, et al.BNIP3 interacting with LC3 triggers excessive mitophagy in delayed neuronal death in stroke.CNS Neurosci Ther, 4,0(12):1045-1055.
    [5] JIN J Y, WEI X X, ZHI X L, et al.DRP1-dependent mitochondrial fission in cardiovascular disease.Acta Pharmacol Sin, 1,2(5):655-664.
    [6] ONG S B, HAUSENLOY D J.Mitochondrial dynamics as a therapeutic target for treating cardiac diseases.Handb Exp Pharmacol, 7,0:251-279.
    [7] ONG S B, SUBRAYAN S, LIM S Y, et al.Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury.Circulation, 0,1(18):2012-2022.
    [8] LIU J X, YAN W, ZHAO X J, et al.Sirt3 attenuates post-infarction cardiac injury via inhibiting mitochondrial fission and normalization of AMPK-DRP1 pathways.Cell Signal, 9,3:1-13.
    [9] PEI H F, DU J, SONG X F, et al.Melatonin prevents adverse myocardial infarction remodeling via Notch1/Mfn2 pathway.Free Radic Biol Med, 6,7:408-417.
    [10] WEN Y D, WANG H, ZHU Y Z.The drug developments of hydrogen sulfide on cardiovascular disease.Oxid Med Cell Longev, 8,8:4010395.
    [11] LIU M J, LI Z N, LIANG B, et al.Hydrogen sulfide ameliorates rat myocardial fibrosis induced by thyroxine through PI3K/AKT signaling pathway.Endocr J, 8,5(7):769-781.
    [12] LI Y L, LIU M J, SONG X, et al.Exogenous hydrogen sulfide ameliorates diabetic myocardial fibrosis by inhibiting cell aging through SIRT6/AMPK autophagy.Front Pharmacol, 0,1:1150.
    [13] LI Z, XIA H J, SHARP T E 3, et al.Mitochondrial H2S regulates BCAA catabolism in heart failure.Circ Res, 2,1(3):222-235.
    [14] SZCZESNY B, MDIS K, YANAGI K, et al.AP39, a novel mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro.Nitric Oxide, 4,1:120-130.
    [15] WEPLER M, MERZ T, WACHTER U, et al.The mitochondria-targeted H2S-donor AP39 in a murine model of combined hemorrhagic shock and blunt chest trauma.Shock, 9,2(2):230-239.
    [16] KARWI Q G, BORNBAUM J, BOENGLER K, et al.AP39, a mitochondria-targeting hydrogen sulfide (H2S) donor, protects against myocardial reperfusion injury independently of salvage kinase signalling.Br J Pharmacol, 7,4(4):287-301.
    [17] GHOSH R, GILLASPIE J J, CAMPBELL K S, et al.Chaperone-mediated autophagy protects cardiomyocytes against hypoxic-cell death.Am J Physiol Cell Physiol, 2,3(5):C1555-C1575.
    [18] IBRAHIM M A, GEDDAWY A, ABDEL-WAHAB S.Sitagliptin prevents isoproterenol-induced myocardial infarction in rats by modulating nitric oxide synthase enzymes.Eur J Pharmacol, 8,9:63-69.
    [19] LI Y L, LIU M J, YI J L, et al.Exogenous hydrogen sulfide inhibits apoptosis by regulating endoplasmic reticulum stress-autophagy axis and improves myocardial reconstruction after acute myocardial infarction.Acta Biochim Biophys Sin (Shanghai), 0,2(12):1325-1336.
    [20] 吴忱昊, 谢志忠.线粒体源性硫化氢及其对线粒体功能的影响.中国动脉硬化杂志, 1,9(4):277-285.WU C H, XIE Z Z.Mitochondrial hydrogen sulfide and its effect on mitochondrial function.Chin J Arterioscler, 1,9(4):277-285.
    [21] FRANGOGIANNIS N G.Regulation of the inflammatory response in cardiac repair.Circ Res, 2,0(1):159-173.
    [22] ZHANG L, JIAN X, YU J, et al.Pterostilbene interferes with lipopolysaccharide-induced myocardial injury through oxidative stress and inflammasome pathways.Front Physiol, 2,3:862187.
    [23] YANG R, JIA Q, MA S F, et al.Exogenous H2S mitigates myocardial fibrosis in diabetic rats through suppression of the canonical Wnt pathway.Int J Mol Med, 9,4(2):549-558.
    [24] LI Y L, CHANDRA T P, SONG X, et al.H2S improves doxorubicin-induced myocardial fibrosis by inhibiting oxidative stress and apoptosis via Keap1-Nrf2.Technol Health Care, 1,9(S1):195-209.
    [25] QI B C, SONG L Q, HU L, et al.Cardiac-specific overexpression of Ndufs1 ameliorates cardiac dysfunction after myocardial infarction by alleviating mitochondrial dysfunction and apoptosis.Exp Mol Med, 2,4(7):946-960.
    [26] LIN L C, TU B, SONG K, et al.Mitochondrial quality control in cardiac fibrosis:epigenetic mechanisms and therapeutic strategies.Metabolism, 3,5:155626.
    [27] LIU D H, ZOU S R, LI G N, et al.Downregulation of uncoupling protein 2(UCP2) mediated by microRNA-762 confers cardioprotection and participates in the regulation of dynamic mitochondrial homeostasis of dynamin related protein1 (DRP1) after myocardial infarction in mice.Front Cardiovasc Med, 1,8:764064.
    [28] ZHOU J R, LIU H H, ZHANG T A, et al.MORN4 protects cardiomyocytes against ischemic injury via MFN2-mediated mitochondrial dynamics and mitophagy.Free Radic Biol Med, 3,6:156-170.
    [29] HUANG B Y, XIE L, KE M, et al.Programmed release METTL3-14 inhibitor microneedle protects myocardial function by reducing Drp1 m6A modification-mediated mitochondrial fission.ACS Appl Mater Interfaces, 3,5(40):46583-46597.
    [30] SINGH M, PUSHPAKUMAR S, ZHENG Y T, et al.Hydrogen sulfide mitigates skeletal muscle mitophagy-led tissue remodeling via epigenetic regulation of the gene writer and eraser function.Physiol Rep, 2,0(16):e15422.
    [31] RAO G, MURPHY B, DEY A, et al.Cystathionine beta synthase regulates mitochondrial dynamics and function in endothelial cells.FASEB J, 0,4(7):9372-9392.
    [32] LEE S W, HU Y S, HU L F, et al.Hydrogen sulphide regulates calcium homeostasis in microglial cells.Glia, 6,4(2):116-124.
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YANG Ting, LAI Qi, YANG Jun, CHU Chun. Effect of the mitochondrial H2S donor AP39 on myocardial fibrosis in rats with myocardial infarction and its relationship to mitochondrial dynamics[J]. Editorial Office of Chinese Journal of Arteriosclerosis,2024,32(6):473-480.

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History
  • Received:August 29,2023
  • Revised:March 03,2024
  • Online: July 04,2024
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