24-脱氢胆固醇还原酶（DHCR24）的高mRNA表达在大鼠阿霉素诱导的心力衰竭治疗中的作用
High mRNA Expression of 24 Dehydrocholesterol Reductase (DHCR24) in the Treatment of Doxorubicin-Induced Heart Failure in Rats.
作者信息
Zhang Rui, Peng Siyuan, Zhang Xuejuan, Huang Zhengwei, Pan Xin
机构信息
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510275, China.
National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
出版信息
Int J Mol Sci. 2025 Jan 1;26(1):312. doi: 10.3390/ijms26010312.
OBJECTIVE
The objective of this study was to explore the possibility of treating heart failure in rats by delivering mRNA of 24-dehydrocholesterol reductase (DHCR24) into the body through lipid nanoparticles (LNPs).
METHODS
We established a heart failure rat model using doxorubicin. The experiment was divided into blank, model, mRNA stock solution cardiac injection, mRNA stock solution intravenous injection, LNP-mRNA stock solution cardiac injection, and LNP-mRNA stock solution intravenous injection groups. We directly injected DHCR24-mRNA or LNP-DHCR24-mRNA into the myocardium in three regions through an insulin needle passing through the intercostal space under the guidance of B-ultrasound. We recorded the mortality rate, body weight, 6-min walk test return times, and organ weight of rats after administration and detected the cardiac structure and function using B-ultrasound and transmission electron microscopy (TEM). Additionally, we tested for HE staining; PRDX2, Sirt3, and TRX1 protein expression; and IL-1 β, IL-10, VEGF, NT proBNP, and BNP cytokine concentrations.
RESULTS
Compared with the model group, the administration of DHCR24-mRNA significantly reduced mortality; decreased weight loss, the ratio of heart to tibia length, and spleen weight; and improved rat motility. The administration of DHCR24-mRNA can postpone the pathological morphological alterations of myocardial cells and reduce inflammatory infiltration. In terms of biochemistry, the administration of DHCR24-mRNA can increase the expression of the PRDX2, Sirt3, and TRX1 proteins; increase the concentrations of IL-10 and VEGF; and reduce the concentrations of IL-1β, NT proBNP, and BNP. The administration of DHCR24-mRNA can also delay the process of heart failure. The delivery and therapeutic effect of DHCR24-mRNA encapsulated in LNPs were better when compared to the other groups.
CONCLUSIONS
DHCR24-mRNA encapsulated in LNPs can be effectively administered to rats with heart failure and exhibits some curative effects.
目的
本研究旨在探讨通过脂质纳米颗粒（LNPs）将24-脱氢胆固醇还原酶（DHCR24）的mRNA导入体内治疗大鼠心力衰竭的可能性。
方法
我们使用阿霉素建立了心力衰竭大鼠模型。实验分为空白组、模型组、mRNA储备液心脏注射组、mRNA储备液静脉注射组、LNP-mRNA储备液心脏注射组和LNP-mRNA储备液静脉注射组。在B超引导下，通过肋间的胰岛素针在三个区域将DHCR24-mRNA或LNP-DHCR24-mRNA直接注射到心肌中。我们记录了给药后大鼠的死亡率、体重、6分钟步行试验返回时间和器官重量，并使用B超和透射电子显微镜（TEM）检测心脏结构和功能。此外，我们进行了苏木精-伊红（HE）染色检测；PRDX2、Sirt3和TRX1蛋白表达检测；以及白细胞介素-1β（IL-1β）、白细胞介素-10（IL-10）、血管内皮生长因子（VEGF）、N末端脑钠肽前体（NT proBNP）和脑钠肽（BNP）细胞因子浓度检测。
结果
与模型组相比，给予DHCR24-mRNA可显著降低死亡率；减少体重减轻、心脏与胫骨长度之比以及脾脏重量；并改善大鼠运动能力。给予DHCR24-mRNA可延缓心肌细胞的病理形态学改变并减少炎症浸润。在生物化学方面，给予DHCR24-mRNA可增加PRDX2、Sirt3和TRX1蛋白的表达；增加IL-10和VEGF的浓度；并降低IL-1β、NT proBNP和BNP的浓度。给予DHCR24-mRNA还可延缓心力衰竭进程。与其他组相比，包裹在LNPs中的DHCR24-mRNA的递送和治疗效果更好。
结论
包裹在LNPs中的DHCR24-mRNA可有效给予心力衰竭大鼠并表现出一定的治疗效果。
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