Jin Xiao-Ping, Ren Yi-Fei, Wang Li-Guo, Xie Hao, Huang Lu, Zhang Juan, Hu Zuo-Ying
Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
These authors contributed equally to this work.
Iran J Basic Med Sci. 2025;28(2):245-253. doi: 10.22038/ijbms.2024.78688.17016.
The close relationship of proto-oncogenes to myocardial hypertrophy has long been recognized, and cardiac hypertrophy leads to heart failure (HF). However, whether proviral insertion of Moloney virus 3 kinase (Pim3), a proto-oncogene, contributes to cardiac hypertrophy in diabetes mellitus (DM) remains unknown. This study aims to investigate whether Pim3 is involved in DM-induced cardiac hypertrophy and HF and to elucidate its underlying mechanisms.
DM was induced in mice by intraperitoneal injection of streptozotocin. Cardiac function was evaluated by echocardiography, and cardiac hypertrophy was determined through histological analysis, quantitative real-time polymerase chain reaction, and western blotting. Silencing RNA transfection and lentivirus-mediated gene knockdown were performed both in vitro and in vivo. Transcriptional activity was analyzed using chromatin immunoprecipitation and luciferase reporter assay.
Compared with C57BL/6J mice, cardiac hypertrophy and dysfunction were observed in mice with DM. Pim3 mRNA and protein expression were significantly up-regulated in diabetic hearts and high glucose-cultured H9C2 cells. Yin Yang 1 (YY1), which translocated from the cytoplasm into the nucleus under hyperglycemia, bound to the Pim3 promoter and enhanced Pim3 transcriptional activity. Pim3 or YY1 knockdown profoundly reduced cell size and inhibited the mRNA and protein expression of cardiac hypertrophy markers, as well as markedly attenuating myocardial hypertrophy and cardiac dysfunction.
Hyperglycemia induced nuclear translocation of YY1, leading to Pim3 up-regulation, eventually developing into cardiac hypertrophy and HF. Targeting YY1-Pim3 signaling may be a promising therapeutic avenue for DM-induced cardiac hypertrophy and HF.
原癌基因与心肌肥大的密切关系早已为人所知，而心脏肥大可导致心力衰竭（HF）。然而，原癌基因莫洛尼病毒3激酶（Pim3）的前病毒插入是否导致糖尿病（DM）患者的心脏肥大仍不清楚。本研究旨在探讨Pim3是否参与糖尿病诱导的心脏肥大和心力衰竭，并阐明其潜在机制。
通过腹腔注射链脲佐菌素诱导小鼠患糖尿病。通过超声心动图评估心脏功能，并通过组织学分析、定量实时聚合酶链反应和蛋白质印迹法确定心脏肥大情况。在体外和体内均进行了RNA干扰转染和慢病毒介导的基因敲低。使用染色质免疫沉淀和荧光素酶报告基因检测分析转录活性。
与C57BL/6J小鼠相比，糖尿病小鼠出现了心脏肥大和功能障碍。糖尿病心脏和高糖培养的H9C2细胞中Pim3 mRNA和蛋白表达显著上调。在高血糖状态下从细胞质转移到细胞核的阴阳1（YY1）与Pim3启动子结合并增强Pim3转录活性。敲低Pim3或YY1可显著减小细胞大小，抑制心脏肥大标志物的mRNA和蛋白表达，并明显减轻心肌肥大和心脏功能障碍。
高血糖诱导YY1核转位，导致Pim3上调，最终发展为心脏肥大和心力衰竭。靶向YY-1-Pim3信号通路可能是治疗糖尿病性心脏肥大和心力衰竭的一个有前景的治疗途径。
