S-propargyl-cysteine (SPRC) is an endogenous hydrogen sulfide (H2S) donor obtained by modifying the structure of S-allyl cysteine in garlic. This study aims to investigate the effect of SPRC on mitigating cardiac aging and the involvement of jumonji domain-containing protein 3 (JMJD3), a histone demethylase, which represents the primary risk factor in major aging related diseases, in this process, elucidating the preliminary mechanism through which SPRC regulation of JMJD3 occurs.
Results:
In vitro, SPRC mitigated the elevated levels of reactive oxygen species, senescence-associated β-galactosidase, p53, and p21, reversing the decline in mitochondrial membrane potential, which represented a reduction in cellular senescence. In vivo, SPRC improved Dox-induced cardiac pathological structure and function. Overexpression of JMJD3 accelerated cardiomyocytes and cardiac senescence, whereas its knockdown in vitro reduced the senescence phenotype. The potential binding site of the upstream transcription factor of JMJD3, sheared X box binding protein 1 (XBP1s), was determined using online software. SPRC promoted the expression of cystathionine γ-lyase (CSE), which subsequently inhibited the IRE1α/XBP1s signaling pathway and decreased JMJD3 expression.
Innovations:
This study is the first to establish JMJD3 as a crucial regulator of cardiac aging. SPRC can alleviate cardiac aging by upregulating CSE and inhibiting endoplasmic reticulum stress pathways, which in turn suppress JMJD3 expression.
Conclusions:
JMJD3 plays an essential role in cardiac aging regulation, whereas SPRC can suppress the expression of JMJD3 by upregulating CSE, thus delaying cardiac aging, which suggests that SPRC may serve as an aging protective agent, and pharmacological targeting of JMJD3 may also be a promising therapeutic approach in age-related heart diseases. Antioxid. Redox Signal. 42, 301–320.
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References
1.
AggerK, CloosPA, RudkjaerL, et al.The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev, 2009; 23(10):1171–1176; doi: 10.1101/gad.510809
2.
Aging Biomarker Consortium, ZhangW, CheY, et al.A biomarker framework for cardiac aging: The aging biomarker consortium consensus statement. Life Medicine, 2023; 2(5):lnad035; doi: 10.1093/lifemedi/lnad035
3.
AlmanzaA, CarlessoA, ChinthaC, et al.Endoplasmic reticulum stress signalling—from basic mechanisms to clinical applications. Febs J, 2019; 286(2):241–278; doi: 10.1111/febs.14608
4.
AltieriP, BarisioneC, LazzariniE, et al.Testosterone antagonizes doxorubicin-induced senescence of Cardiomyocytes. J Am Heart Assoc, 2016; 5(1); doi: 10.1161/jaha.115.002383
AuduCO, MelvinWJ, JoshiAD, et al.Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair. Cell Mol Immunol, 2022; 19(11):1251–1262; doi: 10.1038/s41423-022-00919-5
7.
BarradasM, AndertonE, AcostaJC, et al.Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev, 2009; 23(10):1177–1182; doi: 10.1101/gad.511109
8.
BiranA, ZadaL, Abou KaramP, et al.Quantitative identification of senescent cells in aging and disease. Aging Cell, 2017; 16(4):661–671; doi: 10.1111/acel.12592
9.
BrandãoSR, Reis-MendesA, DominguesP, et al.Exploring the aging effect of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine model. Toxicology, 2021; 459:152852; doi: 10.1016/j.tox.2021.152852
10.
BuenoM, PapazoglouA, ValenziE, et al.Mitochondria, aging, and cellular senescence: Implications for scleroderma. Curr Rheumatol Rep, 2020; 22(8):37; doi: 10.1007/s11926-020-00920-9
11.
BurchfieldJS, LiQ, WangHY, et al.JMJD3 as an epigenetic regulator in development and disease. Int J Biochem Cell Biol, 2015; 67:148–157; doi: 10.1016/j.biocel.2015.07.006
12.
CaiY, LiuH, SongE, et al.Deficiency of telomere-associated repressor activator protein 1 precipitates cardiac aging in mice via p53/PPARα signaling. Theranostics, 2021; 11(10):4710–4727; doi: 10.7150/thno.51739
13.
CaiY, SongW, LiJ, et al.The landscape of aging. Sci China Life Sci, 2022; 65(12):2354–2454; doi: 10.1007/s11427-022-2161-3
14.
ChaddaKR, AjijolaOA, VaseghiM, et al.Ageing, the autonomic nervous system and arrhythmia: From brain to heart. Ageing Res Rev, 2018; 48:40–50; doi: 10.1016/j.arr.2018.09.005
15.
ChenH, LinX, YiX, et al.SIRT1-mediated p53 deacetylation inhibits ferroptosis and alleviates heat stress-induced lung epithelial cells injury. Int J Hyperthermia, 2022; 39(1):977–986; doi: 10.1080/02656736.2022.2094476
16.
ChiaoYA, RabinovitchPS. The aging heart. Cold Spring Harb Perspect Med, 2015; 5(9):a025148; doi: 10.1101/cshperspect.a025148
17.
ChuikovS, KurashJK, WilsonJR, et al.Regulation of p53 activity through lysine methylation. Nature, 2004; 432(7015):353–360; doi: 10.1038/nature03117
18.
CoppéJP, PatilCK, RodierF, et al.Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol, 2008; 6(12):2853–2868; doi: 10.1371/journal.pbio.0060301
19.
De SantaF, TotaroMG, ProsperiniE, et al.The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell, 2007; 130(6):1083–1094; doi: 10.1016/j.cell.2007.08.019
20.
EneCI, EdwardsL, RiddickG, et al.Histone demethylase Jumonji D3 (JMJD3) as a tumor suppressor by regulating p53 protein nuclear stabilization. PLoS One, 2012; 7(12):e51407; doi: 10.1371/journal.pone.0051407
21.
González-GualdaE, BakerAG, FrukL, et al.A guide to assessing cellular senescence in vitro and in vivo. Febs J, 2021; 288(1):56–80; doi: 10.1111/febs.15570
22.
GorgoulisV, AdamsPD, AlimontiA, et al.Cellular senescence: Defining a path forward. Cell, 2019; 179(4):813–827; doi: 10.1016/j.cell.2019.10.005
HackerTA, McKiernanSH, DouglasPS, et al.Age-related changes in cardiac structure and function in Fischer 344 x Brown Norway hybrid rats. Am J Physiol Heart Circ Physiol, 2006; 290(1):H304–H311; doi: 10.1152/ajpheart.00290.2005
25.
HaigisMC, SinclairDA. Mammalian sirtuins: Biological insights and disease relevance. Annu Rev Pathol, 2010; 5:253–295; doi: 10.1146/annurev.pathol.4.110807.092250
26.
HallJA, DominyJE, LeeY, et al.The sirtuin family’s role in aging and age-associated pathologies. J Clin Invest, 2013; 123(3):973–979; doi: 10.1172/jci64094
HuJ, LeisegangMS, LoosoM, et al.Disrupted binding of cystathionine γ-Lyase to p53 promotes endothelial senescence. Circ Res, 2023; 133(10):842–857; doi: 10.1161/CIRCRESAHA.123.323084
29.
HuangJ, SenguptaR, EspejoAB, et al.p53 is regulated by the lysine demethylase LSD1. Nature, 2007; 449(7158):105–108; doi: 10.1038/nature06092
30.
KennedyBK, BergerSL, BrunetA, et al.Geroscience: Linking aging to chronic disease. Cell, 2014; 159(4):709–713; doi: 10.1016/j.cell.2014.10.039
31.
KuilmanT, MichaloglouC, MooiWJ, et al.The essence of senescence. Genes Dev, 2010; 24(22):2463–2479; doi: 10.1101/gad.1971610
32.
KuilmanT, MichaloglouC, VredeveldLC, et al.Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell, 2008; 133(6):1019–1031; doi: 10.1016/j.cell.2008.03.039
33.
LeeSH, KimO, KimHJ, et al.Epigenetic regulation of TGF-β-induced EMT by JMJD3/KDM6B histone H3K27 demethylase. Oncogenesis, 2021; 10(2):17; doi: 10.1038/s41389-021-00307-0
34.
LiY, ChandraTP, SongX, et al.H2S improves doxorubicin-induced myocardial fibrosis by inhibiting oxidative stress and apoptosis via Keap1-Nrf2. Technol Health Care, 2021; 29(S1):195–209; doi: 10.3233/thc-218020
35.
LiangYH, ShenYQ, GuoW, et al.SPRC protects hypoxia and re-oxygenation injury by improving rat cardiac contractile function and intracellular calcium handling. Nitric Oxide, 2014; 41:113–119; doi: 10.1016/j.niox.2014.05.010
36.
LindersAN, DiasIB, López FernándezT, et al.A review of the pathophysiological mechanisms of doxorubicin-induced cardiotoxicity and aging. NPJ Aging, 2024; 10(1):9; doi: 10.1038/s41514-024-00135-7
37.
LiuC, GuX, ZhuYZ. Synthesis and biological evaluation of novel leonurine-SPRC conjugate as cardioprotective agents. Bioorg Med Chem Lett, 2010; 20(23):6942–6946; doi: 10.1016/j.bmcl.2010.09.135
38.
LiuMH, LinXL, ZhangY, et al.Hydrogen sulfide attenuates doxorubicin-induced cardiotoxicity by inhibiting reactive oxygen species-activated extracellular signal-regulated kinase 1/2 in H9c2 cardiac myocytes. Mol Med Rep, 2015; 12(5):6841–6848; doi: 10.3892/mmr.2015.4234
39.
LiuJ, MesfinFM, HunterCE, et al.Recent development of the molecular and cellular mechanisms of hydrogen sulfide gasotransmitter. Antioxidants (Basel), 2022; 11(9); doi: 10.3390/antiox11091788
40.
LongF, WangQ, YangD, et al.Targeting JMJD3 histone demethylase mediates cardiac fibrosis and cardiac function following myocardial infarction. Biochem Biophys Res Commun, 2020; 528(4):671–677; doi: 10.1016/j.bbrc.2020.05.115
41.
López-OtínC, BlascoMA, PartridgeL, et al.The hallmarks of aging. Cell, 2013; 153(6):1194–1217; doi: 10.1016/j.cell.2013.05.039
42.
LuoX, YangD, WuW, et al.Critical role of histone demethylase Jumonji domain-containing protein 3 in the regulation of neointima formation following vascular injury. Cardiovasc Res, 2018; 114(14):1894–1906; doi: 10.1093/cvr/cvy176
43.
MaS, XuL, ChenL, et al.Novel pharmacological inhibition of JMJD3 improves necrotizing enterocolitis by attenuating the inflammatory response and ameliorating intestinal injury. Biochem Pharmacol, 2022; 203:115165; doi: 10.1016/j.bcp.2022.115165
44.
MochidaK, NakatogawaH. ER-phagy: Selective autophagy of the endoplasmic reticulum. EMBO Rep, 2022; 23(8):e55192; doi: 10.15252/embr.202255192
O’RourkeMF, SafarME, DzauV. The cardiovascular continuum extended: Aging effects on the aorta and microvasculature. Vasc Med, 2010; 15(6):461–468; doi: 10.1177/1358863x10382946
47.
PanLL, LiuXH, GongQH, et al.S-Propargyl-Cysteine (SPRC) attenuated lipopolysaccharide-induced inflammatory response in H9c2 cells involved in a hydrogen sulfide-dependent mechanism. Amino Acids, 2011; 41(1):205–215; doi: 10.1007/s00726-011-0834-1
48.
RodierF, MuñozDP, TeachenorR, et al.DNA-SCARS: Distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J Cell Sci, 2011; 124(Pt 1):68–81; doi: 10.1242/jcs.071340
49.
RothGA, MensahGA, JohnsonCO, et al.Global burden of cardiovascular diseases and risk factors, 1990-2019: Update from the GBD 2019 Study. J Am Coll Cardiol, 2020; 76(25):2982–3021; doi: 10.1016/j.jacc.2020.11.010
50.
SalminenA, KaarnirantaK, HiltunenM, et al.Histone demethylase Jumonji D3 (JMJD3/KDM6B) at the nexus of epigenetic regulation of inflammation and the aging process. J Mol Med (Berl), 2014; 92(10):1035–1043; doi: 10.1007/s00109-014-1182-x
51.
SenftD, RonaiZA. UPR, autophagy, and mitochondria crosstalk underlies the ER stress response. Trends Biochem Sci, 2015; 40(3):141–148; doi: 10.1016/j.tibs.2015.01.002
52.
SerranoM, LinAW, McCurrachME, et al.Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell, 1997; 88(5):593–602; doi: 10.1016/s0092-8674(00)81902-9
53.
Sherry-LynesMM, SenguptaS, KulkarniS, et al.Regulation of the JMJD3 (KDM6B) histone demethylase in glioblastoma stem cells by STAT3. PLoS One, 2017; 12(4):e0174775; doi: 10.1371/journal.pone.0174775
54.
ShibuyaN, KoikeS, TanakaM, et al.A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells. Nat Commun, 2013; 4:1366; doi: 10.1038/ncomms2371
SoláS, XavierJM, SantosDM, et al.p53 interaction with JMJD3 results in its nuclear distribution during mouse neural stem cell differentiation. PLoS One, 2011; 6(3):e18421; doi: 10.1371/journal.pone.0018421
57.
SpallarossaP, AltieriP, AloiC, et al.Doxorubicin induces senescence or apoptosis in rat neonatal cardiomyocytes by regulating the expression levels of the telomere binding factors 1 and 2. Am J Physiol Heart Circ Physiol, 2009; 297(6):H2169–H2181; doi: 10.1152/ajpheart.00068.2009
58.
SunN, YouleRJ, FinkelT. The mitochondrial basis of aging. Mol Cell, 2016; 61(5):654–666; doi: 10.1016/j.molcel.2016.01.028
59.
SunT, ZhangL, FengJ, et al.Characterization of cellular senescence in doxorubicin-induced aging mice. Exp Gerontol, 2022; 163:111800; doi: 10.1016/j.exger.2022.111800
60.
TangY, LiT, LiJ, et al.Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease. Cell Death Differ, 2014; 21(3):369–380; doi: 10.1038/cdd.2013.159
61.
TestaiL, BrancaleoneV, FloriL, et al.Modulation of EndMT by hydrogen sulfide in the prevention of cardiovascular fibrosis. Antioxidants (Basel), 2021; 10(6); doi: 10.3390/antiox10060910
62.
WangJC, BennettM. Aging and atherosclerosis: Mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res, 2012; 111(2):245–259; doi: 10.1161/circresaha.111.261388
63.
WangM, GuoZ, WangS. Cystathionine gamma-lyase expression is regulated by exogenous hydrogen peroxide in the mammalian cells. Gene Expr, 2012; 15(5–6):235–241; doi: 10.3727/105221613x13571653093286
64.
WangJ, JiaG, LiH, et al.H(2)O(2)-Mediated oxidative stress enhances cystathionine γ-Lyase-Derived H(2)S synthesis via a sulfenic acid intermediate. Antioxidants (Basel), 2021a;10(9); doi: 10.3390/antiox10091488
65.
WangY, XuJ, ChengZ. YAP1 promotes high glucose-induced inflammation and extracellular matrix deposition in glomerular mesangial cells by modulating NF-κB/JMJD3 pathway. Exp Ther Med, 2021b;22(6):1349; doi: 10.3892/etm.2021.10784
66.
WangY, YingX, WangY, et al.Hydrogen sulfide alleviates mitochondrial damage and ferroptosis by regulating OPA3–NFS1 axis in doxorubicin-induced cardiotoxicity. Cell Signal, 2023; 107:110655; doi: 10.1016/j.cellsig.2023.110655
67.
WangS, ZhangX, HouY, et al.SIRT6 activates PPARα to improve doxorubicin-induced myocardial cell aging and damage. Chem Biol Interact, 2024; 392:110920; doi: 10.1016/j.cbi.2024.110920
68.
WenYD, ZhuYZ. The Pharmacological Effects of S-Propargyl-Cysteine, a Novel Endogenous H2S-Producing Compound. Handb Exp Pharmacol, 2015; 230:325–336; doi: 10.1007/978-3-319-18144-8_16
69.
WilliamsK, ChristensenJ, RappsilberJ, et al.The histone lysine demethylase JMJD3/KDM6B is recruited to p53 bound promoters and enhancer elements in a p53 dependent manner. PLoS One, 2014; 9(5):e96545; doi: 10.1371/journal.pone.0096545
70.
WuJ, GuoW, LinSZ, et al.Gp130-mediated STAT3 activation by S-propargyl-cysteine, an endogenous hydrogen sulfide initiator, prevents doxorubicin-induced cardiotoxicity. Cell Death Dis, 2016; 7(8):e2339; doi: 10.1038/cddis.2016.209
71.
WuW, QinM, JiaW, et al.Cystathionine-γ-lyase ameliorates the histone demethylase JMJD3-mediated autoimmune response in rheumatoid arthritis. Cell Mol Immunol, 2019; 16(8):694–705; doi: 10.1038/s41423-018-0037-8
72.
WuD, SunY, GuY, et al.Cystathionine γ-lyase S-sulfhydrates SIRT1 to attenuate myocardial death in isoprenaline-induced heart failure. Redox Rep, 2023; 28(1):2174649; doi: 10.1080/13510002.2023.2174649
73.
XiaW, HouM. Mesenchymal stem cells confer resistance to doxorubicin-induced cardiac senescence by inhibiting microRNA-34a. Oncol Lett, 2018; 15(6):10037–10046; doi: 10.3892/ol.2018.8438
74.
XuC, WangL, FozouniP, et al.SIRT1 is downregulated by autophagy in senescence and ageing. Nat Cell Biol, 2020; 22(10):1170–1179; doi: 10.1038/s41556-020-00579-5
75.
YangL, LiDX, CaoBQ, et al.Exercise training ameliorates early diabetic kidney injury by regulating the H(2) S/SIRT1/p53 pathway. Faseb J, 2021; 35(9):e21823; doi: 10.1096/fj.202100219R
76.
YangH, MaoY, TanB, et al.The protective effects of endogenous hydrogen sulfide modulator, S-propargyl-cysteine, on high glucose-induced apoptosis in cardiomyocytes: A novel mechanism mediated by the activation of Nrf2. Eur J Pharmacol, 2015; 761:135–143; doi: 10.1016/j.ejphar.2015.05.001
77.
YarmohammadiF, EbrahimianZ, KarimiG. MicroRNAs target the PI3K/Akt/p53 and the Sirt1/Nrf2 signaling pathways in doxorubicin-induced cardiotoxicity. J Biochem Mol Toxicol, 2023; 37(2):e23261; doi: 10.1002/jbt.23261
78.
Zainol AbidinQH, IdaT, MoritaM, et al.Synthesis of sulfides and persulfides is not impeded by disruption of three canonical enzymes in sulfur metabolism. Antioxidants (Basel), 2023; 12(4); doi: 10.3390/antiox12040868
79.
ZhangB, LiY, LiuN, et al.AP39, a novel mitochondria-targeted hydrogen sulfide donor ameliorates doxorubicin-induced cardiotoxicity by regulating the AMPK/UCP2 pathway. PLoS One, 2024; 19(4):e0300261; doi: 10.1371/journal.pone.0300261
80.
ZhangY, LiT, PanM, et al.SIRT1 prevents cigarette smoking-induced lung fibroblasts activation by regulating mitochondrial oxidative stress and lipid metabolism. J Transl Med, 2022; 20(1):222; doi: 10.1186/s12967-022-03408-5
81.
ZhangS, PanC, ZhouF, et al.Hydrogen Sulfide as a Potential Therapeutic Target in Fibrosis. Oxid Med Cell Longev, 2015; 2015:593407; doi: 10.1155/2015/593407
82.
ZhangJ, ZhaoY, GongN. XBP1 Modulates the aging cardiorenal system by regulating oxidative stress. Antioxidants (Basel), 2023a;12(11); doi: 10.3390/antiox12111933
83.
ZhangY, ZhengY, WangS, et al.Single-nucleus transcriptomics reveals a gatekeeper role for FOXP1 in primate cardiac aging. Protein Cell, 2023b;14(4):279–293; doi: 10.1093/procel/pwac038
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