Generic placeholder image

Current Stem Cell Research & Therapy

Editor-in-Chief

ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

Research Article

Regulation of ROS/inflammasome Axis is Essential for Cardiac Regeneration in Aging Rats Receiving Transplantation of Mesenchymal Stem Cells

Author(s): Wei-Syun Hu, Jing-Yi Chen, Wei-Yu Liao, Chin-Hsien Chang and Tung-Sheng Chen*

Volume 19, Issue 10, 2024

Published on: 28 November, 2023

Page: [1393 - 1401] Pages: 9

DOI: 10.2174/011574888X276612231121065203

Price: $65

Abstract

Background: Aging is a biological and gradual deterioration of function in living organisms. Aging is one of the risk factors for heart disease.

Objective: Although mesenchymal stem cell transplantation shows potential in heart disease treatment, the relationship between stem cell-based therapy and oxidative stress/inflammasome axis regulation remains unclear. This study hypothesized that intervention of stem cells showed protective effect on heart aging induced by D-galactose through regulation of oxidative stress/inflammasome axis.

Methods: An aging animal model was designed to test the above hypothesis. Experimental animals were divided into three groups, including Sham, D-gal (aging rats induced by d-galactose), and D-gal+WJSC (aging rats receiving mesenchymal stem cells).

Results: Compared to the Sham, the experimental results indicate that structural alteration (HE stain and Masson’s Trichrome stain), oxidative stress elevation (increase of TBARS level, expression of gp-91 and suppression of Sirt-1 as well as SOD2), increase of aging marker p53, suppression of cardiogenesis marker Troponin T, and inflammasome related protein markers expression (NLRP3, caspase-1 and IL-1 beta) were significantly observed in D-gal. In contrast, all pathological pathways were significantly improved in D-gal+WJSC when compared to D-gal. In addition, migration of stem cells to aging heart tissues was observed in the D-gal+WJSC group.

Conclusion: These findings suggest that mesenchymal stem cell transplantation effectively ameliorates aging hearts through oxidative stress/inflammasome axis regulation. The results from this study provide clinical potential for stem cell-based therapy in the treatment of aging hearts.

[1]
Go, A.S.; Mozaffarian, D.; Roger, V.L.; Benjamin, E.J.; Berry, J.D.; Blaha, M.J.; Dai, S.; Ford, E.S.; Fox, C.S.; Franco, S.; Fullerton, H.J.; Gillespie, C.; Hailpern, S.M.; Heit, J.A.; Howard, V.J.; Huffman, M.D.; Judd, S.E.; Kissela, B.M.; Kittner, S.J.; Lackland, D.T.; Lichtman, J.H.; Lisabeth, L.D.; Mackey, R.H.; Magid, D.J.; Marcus, G.M.; Marelli, A.; Matchar, D.B.; McGuire, D.K.; Mohler, E.R., III; Moy, C.S.; Mussolino, M.E.; Neumar, R.W.; Nichol, G.; Pandey, D.K.; Paynter, N.P.; Reeves, M.J.; Sorlie, P.D.; Stein, J.; Towfighi, A.; Turan, T.N.; Virani, S.S.; Wong, N.D.; Woo, D.; Turner, M.B. Heart disease and stroke statistics-2014 update: A report from the American Heart Association. Circulation, 2014, 129(3), e28-e292.
[http://dx.doi.org/10.1161/01.cir.0000441139.02102.80] [PMID: 24352519]
[2]
Lakatta, E.G.; Levy, D. Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: Links to heart disease. Circulation, 2003, 107(2), 346-354.
[http://dx.doi.org/10.1161/01.CIR.0000048893.62841.F7] [PMID: 12538439]
[3]
Chen, R.; Chen, H.; Yang, Z.; Zhu, L.; Bei, Y.; Chen, W.; Qiu, Y. Danlou tablet inhibits high-glucose-induced cardiomyocyte apoptosis via the miR-34a-SIRT1 axis. Heliyon, 2023, 9(3), e14479.
[http://dx.doi.org/10.1016/j.heliyon.2023.e14479] [PMID: 36950610]
[4]
Lu, C; Jiang, B; Xu, J; Zhang, X; Jiang, N Neferine protected cardiomyocytes against hypoxia/oxygenation injury through SIRT1/Nrf2/HO-1 signaling. J Biochem Mol Toxicol., 2023, 37(8), e23398.
[http://dx.doi.org/10.1002/jbt.23398]
[5]
Peng, B.; Rao, L.; Yang, J.; Ku, X.; Kong, B.; Shuai, W.; Huang, H. Columbianadin attenuates doxorubicin-induced cardiac injury, oxidative stress, and apoptosis via Sirt1/FOXO1 signaling pathway. Acta Cir. Bras., 2023, 38, e382223.
[http://dx.doi.org/10.1590/acb382223] [PMID: 37377248]
[6]
Lin, H.J.; Ramesh, S.; Chang, Y.M.; Tsai, C.T.; Tsai, C.C.; Shibu, M.A.; Tamilselvi, S.; Mahalakshmi, B.; Kuo, W.W.; Huang, C.Y. D-galactose-induced toxicity associated senescence mitigated by alpinate oxyphyllae fructus fortified adipose-derived mesenchymal stem cells. Environ. Toxicol., 2020.
[http://dx.doi.org/10.1002/tox.23014] [PMID: 32889782]
[7]
Ren, S.; Wang, Y.; Zhang, Y.; Yan, P.; Xiao, D.; Zhao, Y.; Jia, W.; Ding, L.; Dong, H.; Wei, C.; Lin, S.; Lin, Y. Paeoniflorin alleviates AngII-induced cardiac hypertrophy in H9c2 cells by regulating oxidative stress and Nrf2 signaling pathway. Biomed. Pharmacother., 2023, 165, 115253.
[http://dx.doi.org/10.1016/j.biopha.2023.115253] [PMID: 37542855]
[8]
Wang, Y.; Liao, J.; Luo, Y.; Li, M.; Su, X.; Yu, B.; Teng, J.; Wang, H.; Lv, X. Berberine alleviates doxorubicin-induced myocardial injury and fibrosis by eliminating oxidative stress and mitochondrial damage via promoting nrf-2 pathway activation. Int. J. Mol. Sci., 2023, 24(4), 3257.
[http://dx.doi.org/10.3390/ijms24043257] [PMID: 36834687]
[9]
Yang, X.; Liu, Z.; Fang, M.; Zou, T.; Zhang, Z.; Meng, X.; Wang, T.; Meng, H.; Chen, Y.; Duan, Y.; Li, Q. Novel pterostilbene derivatives ameliorate heart failure by reducing oxidative stress and inflammation through regulating Nrf2/NF-κB signaling pathway. Eur. J. Med. Chem., 2023, 258, 115602.
[http://dx.doi.org/10.1016/j.ejmech.2023.115602] [PMID: 37406380]
[10]
Liao, L.Z.; Chen, Z.C.; Wang, S.S.; Liu, W.B.; Zhao, C.L.; Zhuang, X.D. NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging. Aging, 2021, 13(16), 20534-20551.
[http://dx.doi.org/10.18632/aging.203435] [PMID: 34432650]
[11]
Rangasami, V.K.; Nawale, G.; Asawa, K.; Kadekar, S.; Samanta, S.; Nilsson, B.; Ekdahl, K.N.; Miettinen, S.; Hilborn, J.; Teramura, Y.; Varghese, O.P.; Oommen, O.P. Pluronic micelle-mediated tissue factor silencing enhances hemocompatibility, stemness, differentiation potential, and paracrine signaling of mesenchymal stem cells. Biomacromolecules, 2021, 22(5), 1980-1989.
[http://dx.doi.org/10.1021/acs.biomac.1c00070] [PMID: 33813822]
[12]
Lee, T.M.; Harn, H.J.; Chiou, T.W.; Chuang, M.H.; Chen, C.H.; Chuang, C.H.; Lin, P.C.; Lin, S.Z. Host pre-conditioning improves human adipose–derived stem cell transplantation in ageing rats after myocardial infarction: Role of NLRP3 inflammasome. J. Cell. Mol. Med., 2020, 24(21), 12272-12284.
[http://dx.doi.org/10.1111/jcmm.15403] [PMID: 33022900]
[13]
Elnakish, M.T.; Kuppusamy, P.; Khan, M. Stem cell transplantation as a therapy for cardiac fibrosis. J. Pathol., 2013, 229(2), 347-354.
[http://dx.doi.org/10.1002/path.4111] [PMID: 23011894]
[14]
Miteva, K.; Pappritz, K.; Sosnowski, M.; El-Shafeey, M.; Müller, I.; Dong, F.; Savvatis, K.; Ringe, J.; Tschöpe, C.; Van Linthout, S. Mesenchymal stromal cells inhibit NLRP3 inflammasome activation in a model of Coxsackievirus B3-induced inflammatory cardiomyopathy. Sci. Rep., 2018, 8(1), 2820.
[http://dx.doi.org/10.1038/s41598-018-20686-6] [PMID: 29434214]
[15]
Chen, L.; Xia, W.; Hou, M. Mesenchymal stem cells attenuate doxorubicin-induced cellular senescence through the VEGF/Notch/TGF-β signaling pathway in H9c2 cardiomyocytes. Int. J. Mol. Med., 2018, 42(1), 674-684.
[http://dx.doi.org/10.3892/ijmm.2018.3635] [PMID: 29693137]
[16]
Lu, D.Y.; Sun, J.; Zheng, J.; Zheng, L.; Xue, W.N.; Li, C.; He, B.; Wang, Y.L.; Li, Y.J.; Liu, T. Shenxiong glucose injection inhibits H2O2-induced H9c2 cell apoptosis by activating the ERK signaling pathway. Biomed. Pharmacother., 2021, 143, 112114.
[http://dx.doi.org/10.1016/j.biopha.2021.112114] [PMID: 34474350]
[17]
Bo-Htay, C.; Palee, S.; Apaijai, N.; Chattipakorn, S.C.; Chattipakorn, N. Effects of D-galactose-induced ageing on the heart and its potential interventions. J. Cell. Mol. Med., 2018, 22(3), 1392-1410.
[http://dx.doi.org/10.1111/jcmm.13472] [PMID: 29363871]
[18]
Wang, S.; Zhang, X.; Ke, Z.; Wen, X.; Li, W.; Liu, W.; Zhuang, X.; Liao, L. D-galactose-induced cardiac ageing: A review of model establishment and potential interventions. J. Cell. Mol. Med., 2022, 26(21), 5335-5359.
[http://dx.doi.org/10.1111/jcmm.17580] [PMID: 36251271]
[19]
Hu, W.S.; Liao, W.Y.; Chang, C.H.; Chen, T.S. Paracrine IGF-1 activates SOD2 expression and regulates ROS/p53 axis in the treatment of cardiac damage in d-galactose-induced aging rats after receiving mesenchymal stem cells. J. Clin. Med., 2022, 11(15), 4419.
[http://dx.doi.org/10.3390/jcm11154419] [PMID: 35956039]
[20]
Chang, Y.M.; Shibu, M.A.; Chen, C.S.; Tamilselvi, S.; Tsai, C.T.; Tsai, C.C.; Kumar, K.A.; Lin, H.J.; Mahalakshmi, B.; Kuo, W.W.; Huang, C.Y. Adipose derived mesenchymal stem cells along with Alpinia oxyphylla extract alleviate mitochondria-mediated cardiac apoptosis in aging models and cardiac function in aging rats. J. Ethnopharmacol., 2021, 264, 113297.
[http://dx.doi.org/10.1016/j.jep.2020.113297] [PMID: 32841691]
[21]
Fernández-Ortiz, M.; Sayed, R.K.A.; Román-Montoya, Y.; de Lama, M.Á.R.; Fernández-Martínez, J.; Ramírez-Casas, Y.; Florido-Ruiz, J.; Rusanova, I.; Escames, G.; Acuña-Castroviejo, D. Age and chronodisruption in mouse heart: Effect of the NLRP3 inflammasome and melatonin therapy. Int. J. Mol. Sci., 2022, 23(12), 6846.
[http://dx.doi.org/10.3390/ijms23126846] [PMID: 35743288]
[22]
Winicki, N.M.; Nanavati, A.P.; Morrell, C.H.; Moen, J.M.; Axsom, J.E.; Krawczyk, M.; Petrashevskaya, N.N.; Beyman, M.G.; Ramirez, C.; Alfaras, I.; Mitchell, S.J.; Juhaszova, M.; Riordon, D.R.; Wang, M.; Zhang, J.; Cerami, A.; Brines, M.; Sollott, S.J.; de Cabo, R.; Lakatta, E.G. A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan. Front. Cardiovasc. Med., 2023, 9, 1096887.
[http://dx.doi.org/10.3389/fcvm.2022.1096887] [PMID: 36741836]
[23]
Tsai, C.Y.; Shen, C.Y.; Liao, H.T.; Li, K.J.; Lee, H.T.; Lu, C.S.; Wu, C.H.; Kuo, Y.M.; Hsieh, S.C.; Yu, C.L. Molecular and cellular bases of immunosenescence, inflammation, and cardiovascular complications mimicking “inflammaging” in patients with systemic lupus erythematosus. Int. J. Mol. Sci., 2019, 20(16), 3878.
[http://dx.doi.org/10.3390/ijms20163878] [PMID: 31395799]
[24]
Wei, Y.; Jia, S.; Ding, Y.; Xia, S.; Giunta, S. Balanced basal-levels of ROS (redox-biology), and very-low-levels of pro-inflammatory cytokines (cold-inflammaging), as signaling molecules can prevent or slow-down overt-inflammaging, and the aging-associated decline of adaptive-homeostasis. Exp. Gerontol., 2023, 172, 112067.
[http://dx.doi.org/10.1016/j.exger.2022.112067] [PMID: 36535453]
[25]
Li, Q.; Huang, K.; Ma, T.; Lu, S.; Tang, S.; Wu, M.; Yang, H.; Zhong, J. Metoprolol protects against arginine vasopressin-induced cellular senescence in h9c2 cardiomyocytes by regulating the Sirt1/p53/p21 axis. Cardiovasc. Toxicol., 2022, 22(2), 99-107.
[http://dx.doi.org/10.1007/s12012-021-09704-8] [PMID: 34800264]
[26]
Jesel, L.; Abbas, M.; Park, S.H.; Matsushita, K.; Kindo, M.; Hasan, H.; Auger, C.; Sato, C.; Ohlmann, P.; Mazzucotelli, J.P.; Toti, F.; Kauffenstein, G.; Schini-Kerth, V.; Morel, O. Atrial fibrillation progression is associated with cell senescence burden as determined by p53 and p16 expression. J. Clin. Med., 2019, 9(1), 36.
[http://dx.doi.org/10.3390/jcm9010036] [PMID: 31878008]
[27]
Xu, T.; Sun, L.; Shen, X.; Chen, Y.; Yin, Y.; Zhang, J.; Huang, D.; Li, W.; Li, W. NADPH oxidase 2-mediated NLRP1 inflammasome activation involves in neuronal senescence in hippocampal neurons in vitro. Int. Immunopharmacol., 2019, 69, 60-70.
[http://dx.doi.org/10.1016/j.intimp.2019.01.025] [PMID: 30677569]
[28]
Zhang, C.; Wang, J.; Ma, X.; Wang, W.; Zhao, B.; Chen, Y.; Chen, C.; Bihl, J.C. ACE2-EPC-EXs protect ageing ECs against hypoxia/reoxygenation-induced injury through the miR-18a/Nox2/ROS pathway. J. Cell. Mol. Med., 2018, 22(3), 1873-1882.
[http://dx.doi.org/10.1111/jcmm.13471] [PMID: 29363860]
[29]
Xu, X.; Zhang, H.; Li, J.; Chen, Y.; Zhong, W.; Chen, Y.; Ma, X. Combination of EPC-EXs and NPC-EXs with miR-126 and miR-210 overexpression produces better therapeutic effects on ischemic stroke by protecting neurons through the Nox2/ROS and BDNF/TrkB pathways. Exp. Neurol., 2023, 359, 114235.
[http://dx.doi.org/10.1016/j.expneurol.2022.114235] [PMID: 36174747]
[30]
England, J.; Pang, K.L.; Parnall, M.; Haig, M.I.; Loughna, S. Cardiac troponin T is necessary for normal development in the embryonic chick heart. J. Anat., 2016, 229(3), 436-449.
[http://dx.doi.org/10.1111/joa.12486] [PMID: 27194630]
[31]
Sun, F.; Xu, K.; Zhou, J.; Zhang, W.; Duan, G.; Lei, M. Allicin protects against LPS-induced cardiomyocyte injury by activating Nrf2-HO-1 and inhibiting NLRP3 pathways. BMC Cardiovasc. Disord., 2023, 23(1), 410.
[http://dx.doi.org/10.1186/s12872-023-03442-1] [PMID: 37596540]
[32]
Yan, M.; Li, L.; Wang, Q.; Shao, X.; Luo, Q.; Liu, S.; Li, Y.; Wang, D.; Zhang, Y.; Diao, H.; Rong, X.; Guo, J. The Chinese herbal medicine Fufang Zhenzhu Tiaozhi protects against diabetic cardiomyopathy by alleviating cardiac lipotoxicity-induced oxidative stress and NLRP3-dependent inflammasome activation. Biomed. Pharmacother., 2022, 148, 112709.
[http://dx.doi.org/10.1016/j.biopha.2022.112709] [PMID: 35190353]
[33]
Mamdouh Hashiesh, H.; Sheikh, A.; Meeran, M.F.N.; Saraswathiamma, D.; Jha, N.K.; Sadek, B.; Adeghate, E.; Tariq, S.; Al Marzooqi, S.; Ojha, S. β-Caryophyllene, a dietary phytocannabinoid, alleviates diabetic cardiomyopathy in mice by inhibiting oxidative stress and inflammation activating cannabinoid type-2 receptors. ACS Pharmacol. Transl. Sci., 2023, 6(8), 1129-42.
[http://dx.doi.org/10.1021/acsptsci.3c00027] [PMID: 37588762]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy