Abstract
Inflammasome-mediated pyroptosis can aggravate myocardial ischemia/reperfusion injury. Total glucosides of paeony (TGP) is widely used in anti-inflammation. This study investigated the effect of TGP on pyroptosis of hypoxia/reoxygenation (H/R)-induced cardiomyocytes. HL-1 cells were subjected to H/R treatment. H/R-induced cardiomyocytes were treated with TGP at different concentrations (50, 100, and 200 mg/kg). The viability of H/R-induced cardiomyocytes was measured. The levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS) were determined. The activity of caspase-1, the expressions of NLRP3 and GSDMD-N, and the concentrations of IL-1β and IL-18 were examined. miR-181a-5p expression in H/R cardiomyocytes was determined. The targeting relationship between miR-181a-5p and adenylate cyclase 1 (ADCY1) was verified. Functional rescue experiments were performed to verify the effect of miR-181a-5p or ADCY1 on the pyroptosis of H/R cardiomyocytes. TGP enhanced H/R-induced cardiomyocyte viability in a dose-dependent manner, reduced LDH, MDA, and ROS levels, increased SOD level, decreased caspase-1 activity, reduced NLRP3 and GSDMD-N expressions, and inhibited IL-1β and IL-18 concentrations. TGP suppressed miR-181a-5p expression in H/R cardiomyocytes. miR-181a-5p targeted ADCY1. miR-181a-5p overexpression or ADCY1 inhibition reversed the inhibitory effect of TGP on the pyroptosis of H/R cardiomyocytes. Collectively, TGP alleviated the pyroptosis of H/R cardiomyocytes via the miR-181a-5p/ADCY1 axis.
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References
Aachoui Y, Sagulenko V, Miao EA, Stacey KJ (2013) Inflammasome-mediated pyroptotic and apoptotic cell death, and defense against infection. Curr Opin Microbiol 16:319–326. https://doi.org/10.1016/j.mib.2013.04.004
Ansley DM, Wang B (2013) Oxidative stress and myocardial injury in the diabetic heart. J Pathol 229:232–241. https://doi.org/10.1002/path.4113
Benoist L, Chadet S, Genet T, Lefort C, Heraud A, Danila MD, Muntean DM, Baron C, Angoulvant D, Babuty D, Bourguignon T, Ivanes F (2019) Stimulation of P2Y11 receptor protects human cardiomyocytes against Hypoxia/Reoxygenation injury and involves PKCepsilon signaling pathway. Sci Rep 9:11613. https://doi.org/10.1038/s41598-019-48006-6
Carbonell T, Gomes AV (2020) MicroRNAs in the regulation of cellular redox status and its implications in myocardial ischemia-reperfusion injury. Redox Biol 36:101607. https://doi.org/10.1016/j.redox.2020.101607
Chen F, Hu Y, Xie Y, Zhao Z, Ma L, Li Z, Tan W (2020) Total glucosides of paeony alleviate cell apoptosis and inflammation by targeting the long noncoding RNA XIST/MicroRNA-124-3p/ITGB1 axis in renal ischemia/reperfusion injury. Mediators Inflamm 2020:8869511. https://doi.org/10.1155/2020/8869511
Del Re DP, Amgalan D, Linkermann A, Liu Q, Kitsis RN (2019) Fundamental mechanisms of regulated cell death and implications for heart disease. Physiol Rev 99:1765–1817. https://doi.org/10.1152/physrev.00022.2018
Ding S, Liu D, Wang L, Wang G, Zhu Y (2020) Inhibiting MicroRNA-29a protects myocardial ischemia-reperfusion injury by targeting SIRT1 and suppressing oxidative stress and NLRP3-mediated pyroptosis pathway. J Pharmacol Exp Ther 372:128–135. https://doi.org/10.1124/jpet.119.256982
Guo Z, Yu S, Chen X, Ye R, Zhu W, Liu X (2016) NLRP3 is involved in ischemia/reperfusion injury. CNS Neurol Disord Drug Targets 15:699–712. https://doi.org/10.2174/1871527315666160321111829
Hausenloy DJ, Yellon DM (2013) Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest 123:92–100. https://doi.org/10.1172/JCI62874
He RQ, Li XJ, Liang L, Xie Y, Luo DZ, Ma J, Peng ZG, Hu XH, Chen G (2017) The suppressive role of miR-542-5p in NSCLC: the evidence from clinical data and in vivo validation using a chick chorioallantoic membrane model. BMC Cancer 17:655. https://doi.org/10.1186/s12885-017-3646-1
He X, Li S, Fang X, Liao Y (2018) TDCPP protects cardiomyocytes from hypoxia-reoxygenation injury induced apoptosis through mitigating calcium overload and promotion GSK-3beta phosphorylation. Regul Toxicol Pharmacol 92:39–45. https://doi.org/10.1016/j.yrtph.2017.11.005
He Y, Liu J N, Zhang J J, & Fan W (2016) Involvement of microRNA-181a and Bim in a rat model of retinal ischemia-reperfusion injury. Int J Ophthalmol 9:33–40. https://doi.org/10.18240/ijo.2016.01.06
Hu F, Zhang S, Chen X, Fu X, Guo S, Jiang Z, Chen K (2020) MiR-219a-2 relieves myocardial ischemia-reperfusion injury by reducing calcium overload and cell apoptosis through HIF1alpha/ NMDAR pathway. Exp Cell Res 395:112172. https://doi.org/10.1016/j.yexcr.2020.112172
Jackson CR, Chaurasia SS, Hwang CK, Iuvone PM (2011) Dopamine D(4) receptor activation controls circadian timing of the adenylyl cyclase 1/cyclic AMP signaling system in mouse retina. Eur J Neurosci 34:57–64. https://doi.org/10.1111/j.1460-9568.2011.07734.x
Kitaguchi T, Oya M, Wada Y, Tsuboi T, Miyawaki A (2013) Extracellular calcium influx activates adenylate cyclase 1 and potentiates insulin secretion in MIN6 cells. Biochem J 450:365–373. https://doi.org/10.1042/BJ20121022
Lee S, Choi E, Cha MJ, Hwang KC (2015) Looking for pyroptosis-modulating mirnas as a therapeutic target for improving myocardium survival. Mediators Inflamm 2015:254871. https://doi.org/10.1155/2015/254871
Lin J, Lin H, Ma C, Dong F, Hu Y, & Li H (2019) MiR-149 Aggravates Pyroptosis in Myocardial Ischemia-Reperfusion Damage via Silencing FoxO3. Med Sci Monit 25:8733–8743. https://doi.org/10.12659/MSM.918410
Li Y, Li Q, Zhang O, Guan X, Xue Y, Li S, Zhuang X, Zhou B, Miao G (2019) miR-202-5p protects rat against myocardial ischemia reperfusion injury by downregulating the expression of Trpv2 to the Ca (2+) overload in cardiomyocytes. J Cell Biochem 120:13680–13693. https://doi.org/10.1002/jcb.28641
Long J, Gao M, Kong Y, Shen X, Du X, Son YO, Shi X, Liu J, Mo X (2012) Cardioprotective effect of total paeony glycosides against isoprenaline-induced myocardial ischemia in rats. Phytomedicine 19:672–676. https://doi.org/10.1016/j.phymed.2012.03.004
Lu L, Wei P, Cao Y, Zhang Q, Liu M, Liu X D, Wang Z L, & Zhang P Y (2016) Effect of total peony glucoside pretreatment on NF-kappaB and ICAM-1 expression in myocardial tissue of rat with myocardial ischemia-reperfusion injury. Genet Mol Res 15. https://doi.org/10.4238/gmr15048978
Luo C, Wang H, Chen X, Cui Y, Li H, Long J, Mo X, Liu J (2013) Protection of H9c2 rat cardiomyoblasts against oxidative insults by total paeony glucosides from Radix Paeoniae Rubrae. Phytomedicine 21:20–24. https://doi.org/10.1016/j.phymed.2013.08.002
Makhdoumi P, Roohbakhsh A, Karimi G (2016) MicroRNAs regulate mitochondrial apoptotic pathway in myocardial ischemia-reperfusion-injury. Biomed Pharmacother 84:1635–1644. https://doi.org/10.1016/j.biopha.2016.10.073
Miao EA, Rajan JV, Aderem A (2011) Caspase-1-induced pyroptotic cell death. Immunol Rev 243:206–214. https://doi.org/10.1111/j.1600-065X.2011.01044.x
Mo X, Zhao N, Du X, Bai L, Liu J (2011) The protective effect of peony extract on acute myocardial infarction in rats. Phytomedicine 18:451–457. https://doi.org/10.1016/j.phymed.2010.10.003
Patane S, Patane F (2018) Emerging molecular therapies targeting myocardial infarction-related arrhythmias: the role of miRNAs regulation. Europace 20:1058. https://doi.org/10.1093/europace/eux201
Qi M, He L, Ma X, Li Z (2020) MiR-181a-5p is involved in the cardiomyocytes apoptosis induced by hypoxia-reoxygenation through regulating SIRT1. Biosci Biotechnol Biochem 84:1353–1361. https://doi.org/10.1080/09168451.2020.1750943
Qiu Z, He Y, Ming H, Lei S, Leng Y, Xia ZY (2019) Lipopolysaccharide (LPS) aggravates high glucose- and hypoxia/reoxygenation-induced injury through activating ros-dependent NLRP3 inflammasome-mediated pyroptosis in H9C2 cardiomyocytes. J Diabetes Res 2019:8151836. https://doi.org/10.1155/2019/8151836
Qiu Z, Lei S, Zhao B, Wu Y, Su W, Liu M, Meng Q, Zhou B, Leng Y, Xia ZY (2017) NLRP3 inflammasome activation-mediated pyroptosis aggravates myocardial ischemia/reperfusion injury in diabetic rats. Oxid Med Cell Longev 2017:9743280. https://doi.org/10.1155/2017/9743280
Sandanger O, Ranheim T, Vinge LE, Bliksoen M, Alfsnes K, Finsen AV, Dahl CP, Askevold ET, Florholmen G, Christensen G, Fitzgerald KA, Lien E, Valen G, Espevik T, Aukrust P, Yndestad A (2013) The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res 99:164–174. https://doi.org/10.1093/cvr/cvt091
Sethna F, Feng W, Ding Q, Robison AJ, Feng Y, Wang H (2017) Enhanced expression of ADCY1 underlies aberrant neuronal signalling and behaviour in a syndromic autism model. Nat Commun 8:14359. https://doi.org/10.1038/ncomms14359
Shen P, Chen J, Pan M (2018) The protective effects of total paeony glycoside on ischemia/reperfusion injury in H9C2 cells via inhibition of the PI3K/Akt signaling pathway. Mol Med Rep 18:3332–3340. https://doi.org/10.3892/mmr.2018.9335
Shen S, He F, Cheng C, Xu B, Sheng J (2021) Uric acid aggravates myocardial ischemia-reperfusion injury via ROS/NLRP3 pyroptosis pathway. Biomed Pharmacother 133:110990. https://doi.org/10.1016/j.biopha.2020.110990
Swanson KV, Deng M, Ting JP (2019) The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 19:477–489. https://doi.org/10.1038/s41577-019-0165-0
Takahashi M (2013) NLRP3 in myocardial ischaemia-reperfusion injury: inflammasome-dependent or -independent role in different cell types. Cardiovasc Res 99:4–5. https://doi.org/10.1093/cvr/cvt142
Toldo S, Mauro AG, Cutter Z, Abbate A (2018) Inflammasome, pyroptosis, and cytokines in myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 315:H1553–H1568. https://doi.org/10.1152/ajpheart.00158.2018
Tsikas D (2017) Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: Analytical and biological challenges. Anal Biochem 524:13–30. https://doi.org/10.1016/j.ab.2016.10.021
Wang L, Huang H, Fan Y, Kong B, Hu H, Hu K, Guo J, Mei Y, Liu WL (2014) Effects of downregulation of microRNA-181a on H2O2-induced H9c2 cell apoptosis via the mitochondrial apoptotic pathway. Oxid Med Cell Longev 2014:960362. https://doi.org/10.1155/2014/960362
Wang X, Cheng Z, Xu J, Feng M, Zhang H, Zhang L, Qian L (2021) Circular RNA Arhgap12 modulates doxorubicin-induced cardiotoxicity by sponging miR-135a-5p. Life Sci 265:118788. https://doi.org/10.1016/j.lfs.2020.118788
Wang Z (2010) MicroRNA: A matter of life or death. World J Biol Chem 1:41–54. https://doi.org/10.4331/wjbc.v1.i4.41
Yang LX, Li BL, Liu XH, Yuan Y, Lu CJ, Chen R, Zhao J (2014) RNA-seq reveals determinants of sensitivity to chemotherapy drugs in esophageal carcinoma cells. Int J Clin Exp Pathol 7:1524–1533
Yao B, Wan X, Zheng X, Zhong T, Hu J, Zhou Y, Qin A, Ma Y, Yin D (2020) Critical roles of microRNA-141-3p and CHD8 in hypoxia/reoxygenation-induced cardiomyocyte apoptosis. Cell Biosci 10:20. https://doi.org/10.1186/s13578-020-00384-5
Ye B, Chen X, Dai S, Han J, Liang X, Lin S, Cai X, Huang Z, Huang W (2019) Emodin alleviates myocardial ischemia/reperfusion injury by inhibiting gasdermin D-mediated pyroptosis in cardiomyocytes. Drug Des Devel Ther 13:975–990. https://doi.org/10.2147/DDDT.S195412
Zhang L, Wei W (2020) Anti-inflammatory and immunoregulatory effects of paeoniflorin and total glucosides of paeony. Pharmacol Ther 207:107452. https://doi.org/10.1016/j.pharmthera.2019.107452
Zhang L X, Ding F, Wang C Q, Bing Q, Zhao Z, Wang J, & Zhang L (2019) MiR-181a affects myocardial ischemia-reperfusion injury in rats via regulating akt signaling pathway. Eur Rev Med Pharmacol Sci 23:6292–6298. https://doi.org/10.26355/eurrev_201907_18451
Zhang Y, Shan Z, Zhao Y, Ai Y (2019b) Sevoflurane prevents miR-181a-induced cerebral ischemia/reperfusion injury. Chem Biol Interact 308:332–338. https://doi.org/10.1016/j.cbi.2019.06.008
Zhao D, Yang J, Yang L (2017) Insights for Oxidative Stress and mTOR Signaling in Myocardial Ischemia/Reperfusion Injury under Diabetes. Oxid Med Cell Longev 2017:6437467. https://doi.org/10.1155/2017/6437467
Zhuo Y, Chen W, Li W, Huang Y, Duan D, Ge L, He J, Liu J, Hu Z, & Lu M (2021) Ischemic-hypoxic preconditioning enhances the mitochondrial function recovery of transplanted olfactory mucosa mesenchymal stem cells via miR-181a signaling in ischemic stroke. Aging (Albany NY) 13:11234–11256. https://doi.org/10.18632/aging.202807
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Yan, X., Huang, Y. Mechanism of total glucosides of paeony in hypoxia/reoxygenation-induced cardiomyocyte pyroptosis. J Bioenerg Biomembr 53, 643–653 (2021). https://doi.org/10.1007/s10863-021-09921-4
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DOI: https://doi.org/10.1007/s10863-021-09921-4