Dexmedetomidine Preconditioning Mitigates Myocardial Ischemia/Reperfusion Injury via Inhibition of Mast Cell Degranulation

Abstract

Background: The degranulation of cardiac mast cells is associated with the occurrence and development of myocardial ischemia/reperfusion (I/R) injury (MIRI). Dexmedetomidine (DEX) has a cardioprotective effect from I/R injury. The present study investigated whether DEX preconditioning-induced cardioprotection was related to suppression of the degranulation of cardiac mast cells. Methods: The ligation of the left anterior descending coronary artery for 30 min of ischemia and 120 min of reperfusion was used to establish a rat MIRI model in vivo. The MIRI Langendorff model in vitro of rat isolated heart was constructed by global ischemia for 30 min and reperfusion for 60 min. The effect of compound 48/80 (C48/80) and DEX pretreatment on MIRI was then evaluated. Hemodynamics and electrocardiogram were assessed for each rat/heart. TTC staining, hematoxylin-eosin staining, and toluidine blue staining, transmission electron microscope detection, TUNEL staining, ELISA, IHE staining, qRT-PCR, and western blot were detected. Further work was performed using a cell coculture test to verify. Findings: In vivo and in vitro experimental results revealed that hemodynamic disorder, arrhythmia, infarct size, histopathological score, and mast cell degranulation were dramatically increased in the I/R injury groups compared to the non-I/R groups. Mastocyte secretagogue compound 48/80 (C48/80) aggravated these damages, and DEX preconditioning mitigated these damages. C48/80 increased the levels of I/R injury-induced cardiac troponin-1 (cTnI) and tryptase, cardiomyocytes apoptosis, and the expression of high mobility group protein B1 (HMGB1), Toll-like receptor 4 (TLR4), and nuclear factor kappa B (NF-κB) p65 in cardiac tissues, and DEX pretreatment partially reduced these changes. C48/80 inhibited the proliferation of H9C2(2-1) and RBL-2H3, exacerbated apoptosis of H9C2(2-1), and increased the levels of cTnI and tryptase, and DEX pretreatment abolished these changes. Interpretation: Our data suggest that DEX preconditioning alleviates the MIRI-induced degranulation of mast cells and the apoptosis of cardiomyocytes, and inhibits the activation of inflammatory-related factors HMGB1, TLR4, and NF-κB p65. Funding Information: This research was supported by the National Natural Science Foundation of China (81860050 & 82060060), Yunnan Health Training Project of High Levels Talents (L-2018007), Program for Innovative Research Team of Kunming Medical University (CXTD201802), Yunnan Provincial Ten Thousand-Talent Program-Famous Doctor (YNWR-MY-2018-043), Innovative fund of Kunming Medical University (2020D013), and Yunnan Provincial Education Department (2020Y0120). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All experimental procedures were performed in accordance with the guidelines formulated by the Institutional Animal Care and Use Committee of Kunming Medical University (No. KMU20191119).