Levosimendan attenuates suspension-reperfusion injury in isolated hearts of rat models

doi:10.16352/j.issn.1001-6325.2025.01.0065

Abstract

Abstract: Objective To investigate the effect of levosimendan on the cyclic guanosine monophosphate-adenosin monophosphate synthase-interferon gene stimulating factor (cGAS-STING) signaling pathway during suspension-reperfusion in isolated rat myocardium. Methods The rats were divided into four groups (n=12) using random number table: continuous perfusion group (CO group),suspension-reperfusion group(SR group),suspension-reperfusion+levosimendan group (SR-L group), and suspension-reperfusion+levosimendan+STING activator: DMXAA group (SR-LD group). Heart rate (HR), left ventricular end-diastolic pressure (LVEDP), left ventricular developmental pressure (LVDP), maximum rate of increase in left ventricular pressure (+dp/dt_max) and maximum rate of decrease in left ventricular pressure (-dp/dtmax), and Reperfusion Arrhythmia scores were recorded at the end of equilibrium perfusion (T0), 30 min of reperfusion (T1), and 60 min of reperfusion (T2) respectively. Western blot was used to detect cGAS-STING signaling pathway and autophagy-related protein expression. The size of myocardial infarction was measured by using triphenyl tetrazolium chloride (TTC). Results Compared with CO group, SR group had decreased HR, LVDP, +dp/dt_max, and -dp/dt_max at T1 and T2, increase of LVEDP,Reperfusion Arrhythmia score , percentage of myocardial infarcted area, expression of myocardial tissue cGAS and STING proteins and increased LC3 Ⅱ/Ⅰ ratio, while p62 decreased (P＜0.05); compared with SR group, SR-L group cardiac function indexes improved, myocardial tissue cGAS, STING protein expression was down-regulated, LC3 Ⅱ/Ⅰ ratio was decreased, and p62 was elevated (P＜0.05); SR-LD group reversed the improvement of myocardial injury by levosimendan compared with SR-L. Conclusions Levosimendan may protect myocardial tissue by inhibiting the cGAS-STING signaling pathway, down-regulating cardiomyocyte autophagy and reducing myocardial infarction size, so to improve cardial function.

Key words: levosimendan, myocardial ischemia-reperfusion, autophagy, cGAS-STING signaling pathway

CLC Number:

R453

PANG Yunting, REN Xiaoshuang, BAO Han, MENG Fanqing, SHI Feng. Levosimendan attenuates suspension-reperfusion injury in isolated hearts of rat models[J]. Basic & Clinical Medicine, 2025, 45(1): 65-69.

References

[1] Basir MB, Lemor A, Gorgis S, et al. Vasopressors independently associated with mortality in acute myocardial infarction and cardiogenic shock[J]. Catheter Cardiovasc Interv, 2022, 99:650-657. doi: 10.1002/ccd.29895.
[2] Popov SV, Mukhomedzyanov AV, Voronkov NS, et al. Regulation of autophagy of the heart in ischemia and reperfusion[J]. Apoptosis, 2023, 28:55-80. doi: 10.1007/s10495-022-01786-1.
[3] Huang CQ, Andres AM, Ratliff EP, et al. Precondition-ing involves selective mitophagy mediated by Parkin and p62/SQSTM1[J]. PLoS One, 2011, 6:e20975. doi:10.1371/journal.pone.0020975.
[4] Hopfner KP, Hornung V. Molecular mechanisms and cellular functions of cGAS-STING signalling[J]. Nat Rev Mol Cell Biol, 2020,21:501-521. doi:10.1038/s41580-020-0244-x.
[5] Papp Z, Agostoni P, Alvarez J, et al. Levosimendan efficacy and safety: 20 years of SIMDAX in clinical use[J]. J Cardiovasc Pharmacol, 2020, 76:4-22. doi: 10.1097/FJC.0000000000000859.
[6] Vasileios L, Efstratios K, Nikolaos T, et al. The coadministration of levosimendan and exenatide offers a significant cardioprotective effect to isolated rat hearts against ischemia/reperfusion injury[J]. J Cardiovasc Dev Dis, 2022, 9:263-292. doi: 10.3390/jcdd9080263.
[7] He L, Hao S, Wang Y, et al. Dexmedetomidine preconditioning attenuates ischemia/reperfusion injury in isolated rat hearts with endothelial dysfunction[J]. Biomed Pharmacother, 2019, 114:108837. doi: 10.1016/j.biopha.2019.108837.
[8] Walker MJ, Curtis MJ, Hearse DJ, et al. The lambeth conventions: guidelines for the study of arrhythnfias in ischaemia infarction and reperfusion[J]. Cardiovase Res, 1988, 22: 447-455. doi: 10.1093/cvr/22.7.447.
[9] Louhelainen M, Vahtola E, Kaheinen P, et al. Effects of levosimendan on cardiac remodeling and cardiomyo-cyte apoptosis in hypertensive Dahl/Rapp rats[J]. Br. J.Pharmacol, 2007,150: 851-861. doi: 10.1038/sj.bjp.0707157.
[10] Li G, Zhao X, Zheng Z, Zhang. cGAS-STING pathway mediates activation of dendritic cell sensing of immuno-genic tumors[J]. Cell Mol Life Sci, 2024, 81:149. doi: 10.1007/s00018-024-05191-6.
[11] Li JK, Song ZP, Hou XZ. Scutellarin ameliorates ischemia/reperfusion injury-induced cardiomyocyte apoptosis and cardiac dysfunction via inhibition of the cGAS-STING pathway[J]. Exp Ther Med, 2023, 25:155. doi: 10.3892/etm.2023.11854.
[12] 江罗佳, 许海波. 白藜芦醇缓解低氧/复氧诱导的TCMK1细胞线粒体自噬[J]. 基础医学与临床, 2022, 42:1709-1715. doi: 10.16352/j.issn.1001-6325.2022.11.1709.
[13] Song L, Jian MR, Shi YL, et al. Resveratrol inhibits autophagy against myocardial ischemia-reperfusion injury through the DJ-1/MEKK1/JNK pathway[J]. Eur J Pharmacol, 2023, 951:175748. doi: 10.1016/j.ejphar.2023.175748.
[14] Qin GW, Lu P, Peng L, et al. Ginsenoside Rb1 inhibits cardiomyocyte autophagy via PI3K/Akt/mTOR signaling pathway and reduces myocardial ischemia/reperfusion Injury[J]. Am J Chin Med, 2021, 49:1913-1927. doi: 10.1142/S0192415X21500907.
[15] Liu D, Wu H, Wang CG, et al. STING directly activates autophagy to tune the innate immuneresponse[J]. Cell Death Differ, 2019, 26:1735-1749. doi: 10.1038/s41418-018-0251-z. doi: 10.1038/s41418-018-0251-z.