Huang Jie, Hou Xingyuan, Zhou Ni, Su Nan, Wei Shanshan, Yang Yuanying, Sun Taoli, Li Guangdi, Li Wenqun, Zhang Bikui
Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha, 410013, Hunan, China.
Cardiovasc Drugs Ther. 2025 Jan 14. doi: 10.1007/s10557-024-07665-y.
Doxorubicin (Dox) is a classic anthracycline chemotherapy drug with cause cumulative and dose-dependent cardiotoxicity. This study aimed to investigate the potential role and molecular mechanism of phenylacetylglutamine (PAGln), a novel gut microbiota metabolite, in Dox-induced cardiotoxicity (DIC).
DIC models were established in vivo and in vitro, and a series of experiments were performed to verify the cardioprotective effect of PAGln. RNA sequencing (RNA-seq) was employed to explore the mechanism of PAGln in DIC. Subsequently, the differentially expressed genes (DEGs) were subjected to comprehensive analysis using diverse public databases, and RT-PCR was used to confirm the expression levels of the candidate genes. Finally, molecular docking techniques were used for validation.
PAGln effectively prevented both in vivo and in vitro Dox-induced myocardial injury and cell apoptosis. RNA-seq results showed that 40 genes were up-regulated and 54 down-regulated in the Dox group compared to the Con group, displaying opposite changes in the Dox + PAGln group. Enrichment analysis highlighted several mechanisms by which PAGln alleviated Dox-induced cardiotoxicity, including the lipid metabolic process, calcium-mediated signaling, positive regulation of store-operated calcium channel activity, and hypertrophic cardiomyopathy. In vitro and in vivo experiments confirmed that PAGln treatment could reverse the changes in the expression levels of Klb, Ece2, Nmnat2, Casq1, Pak1, and Apob in Dox. Molecular docking results showed that these genes had good binding activity with PAGln.
PAGln shows potential in alleviating Dox-induced cardiotoxicity, with Ece2 identified as key regulatory molecules related to endothelial dysfunction.
阿霉素（Dox）是一种经典的蒽环类化疗药物，会导致累积性和剂量依赖性心脏毒性。本研究旨在探讨新型肠道微生物群代谢产物苯乙酰谷氨酰胺（PAGln）在阿霉素诱导的心脏毒性（DIC）中的潜在作用及分子机制。
在体内和体外建立DIC模型，并进行一系列实验以验证PAGln的心脏保护作用。采用RNA测序（RNA-seq）来探究PAGln在DIC中的作用机制。随后，使用各种公共数据库对差异表达基因（DEGs）进行综合分析，并通过RT-PCR确认候选基因的表达水平。最后，运用分子对接技术进行验证。
PAGln有效预防了体内和体外阿霉素诱导的心肌损伤和细胞凋亡。RNA-seq结果显示，与对照组相比，阿霉素组中有40个基因上调，54个基因下调，而在阿霉素+PAGln组中呈现相反的变化。富集分析突出了PAGln减轻阿霉素诱导的心脏毒性的几种机制，包括脂质代谢过程、钙介导的信号传导、储存性钙通道活性的正调控以及肥厚型心肌病。体内和体外实验证实，PAGln处理可逆转阿霉素处理组中Klb、Ece2、Nmnat2、Casq1、Pak1和Apob表达水平的变化。分子对接结果表明，这些基因与PAGln具有良好的结合活性。
PAGln在减轻阿霉素诱导的心脏毒性方面显示出潜力，其中Ece2被确定为与内皮功能障碍相关的关键调节分子。
