Yuan Chenyue, Wu Zong, Jin Cuiliu, Cao Weiwei, Dong Yaorong, Chen Jiahui, Liu Chenping
Department of Cardiology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Middle Zhijiang Road, Shanghai 200071, China.
Centeral Laboratory, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Middle Zhijiang Road, Shanghai 200071, China.
Phytomedicine. 2023 Apr;112:154697. doi: 10.1016/j.phymed.2023.154697. Epub 2023 Feb 10.
Qiangxin recipe (QXF) is a well-known Chinese herbal medicine commonly used in Asia for thousands of years to treat cardiovascular diseases, but its underlying mechanism remains unclear.
This study aimed to illustrate whether Qiangxin Recipe (QXF) induce glucose metabolism and inhibit cardiomyocyte apoptosis by promoting the activation of the transcription factor Krüppel like factor 5 (KLF5).
In vitro experiments, we constructed an H9C2 cardiomyocyte injury model using doxorubicin and used RNA-seq data analysis to detect the mechanism of QXF. In in vivo experiments, C57 BL/6 mice injected with doxorubicin (4 mg/kg every 6 days, for 30 days) to construct a CHF mouse model and randomly divided into to the normal control group, Dox group and Dox+QXF group (2.12 g/kg/day, 4.24 g/kg/day, for 30 days). Using Echocardiography, serum biochemical indices BNP, cTnl; and histopathological tests involving HE staining, Tunel staining and Immuno-dual fluorescence colocalization to analyze the therapeutic mechanism of QXF.
We verified that the Qiangxin recipe could reverse cardiomyocyte dying through enhancing glucose metabolism and reducing apoptosis to improve CHF. Mechanistically, we discovered that the Qiangxin recipe promoted the activation of transcription factor Krüppel-like factor 5 (KLF5) to induce glucose metabolism and inhibit apoptosis in cardiomyocytes. Further, we identified that KLF5 increased the promoter activity of hexokinase 2 (HK2) and B-cell CLL/lymphoma 2 (BCL2) genes, which further enhanced glucose metabolism and inhibited apoptosis of cardiomyocytes.
We highlighted the importance of KLF5-mediated signaling pathways in the treatment of CHF as shown by their participation in glucose metabolism and apoptosis in a doxorubicin-induced model of cardiomyocyte injury, as well as show that Qiangxin recipe can be used as a novel targeted therapy for the treatment of CHF. Compared with previous studies, we provide new ideas for the treatment of Doxorubicin-induced CHF from the perspective of energy metabolism.
强心方（QXF）是一种著名的中药，在亚洲已被用于治疗心血管疾病数千年，但其潜在机制仍不清楚。
本研究旨在阐明强心方（QXF）是否通过促进转录因子Krüppel样因子5（KLF5）的激活来诱导葡萄糖代谢并抑制心肌细胞凋亡。
在体外实验中，我们用阿霉素构建了H9C2心肌细胞损伤模型，并使用RNA测序数据分析强心方的作用机制。在体内实验中，给C57 BL/6小鼠注射阿霉素（每6天4 mg/kg，共30天）以构建慢性心力衰竭（CHF）小鼠模型，并随机分为正常对照组、阿霉素组和阿霉素+强心方组（2.12 g/kg/天、4.24 g/kg/天，共30天）。使用超声心动图、血清生化指标脑钠肽（BNP）、心肌肌钙蛋白I（cTnl）；以及包括苏木精-伊红（HE）染色、TUNEL染色和免疫双荧光共定位的组织病理学检测来分析强心方的治疗机制。
我们证实强心方可以通过增强葡萄糖代谢和减少凋亡来逆转心肌细胞死亡，从而改善慢性心力衰竭。机制上，我们发现强心方促进转录因子Krüppel样因子5（KLF5）的激活，以诱导葡萄糖代谢并抑制心肌细胞凋亡。此外，我们确定KLF5增加了己糖激酶2（HK2）和B细胞淋巴瘤/白血病-2（BCL2）基因的启动子活性，并进一步增强葡萄糖代谢和抑制心肌细胞凋亡。
我们强调了KLF5介导的信号通路在慢性心力衰竭治疗中的重要性，这体现在它们参与阿霉素诱导的心肌细胞损伤模型中的葡萄糖代谢和凋亡，同时表明强心方可以作为一种新型靶向疗法用于治疗慢性心力衰竭。与以往研究相比，我们从能量代谢的角度为阿霉素诱导的慢性心力衰竭的治疗提供了新思路。
