Zhang Xiao-Nan, Li Yan-Yang, Lyu Shi-Chao, Jia Qiu-Jin, Zhang Jun-Ping, Liu Long-Tao
Department of Cardiovascular Medicine, National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China.
Department of Integrated Traditional Chinese and Western Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
Chin J Integr Med. 2025 Mar;31(3):240-250. doi: 10.1007/s11655-025-4005-8. Epub 2025 Jan 15.
To explore the molecular mechanism of Shenmai Injection (SMI) against doxorubicin (DOX) induced cardiomyocyte apoptosis.
A total of 40 specific pathogen-free (SPF) male Sprague Dawley (SD) male rats were divided into 5 groups based on the random number table, including the control group, the model group, miR-30a agomir group, SMI low-dose (SMI-L) group, and SMI high-dose (SMI-H) group, with 8 rats in each group. Except for the control group, the rats were injected weekly with DOX (2 mg/kg) in the tail vein for 4 weeks to induce myocardial injury, and were given different regimens of continuous intervention for 2 weeks. Cardiac function was detected by echocardiography and myocardial pathological changes were observed by Van Gieson (VG) staining. Myocardial injury serum markers, including creatine kinase (CK), lactate dehydrogenase (LDH), troponin T (cTnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), soluble ST2 (sST2), and growth differentiation factor-15 (GDF-15) were detected by enzyme linked immunosorbent assay (ELISA). Cardiomyocyte apoptosis was observed by terminal deoxynucleotidyl transferase-mediated biotinylated dUTP triphosphate nick end labeling (TUNEL) and transmission electron microscopy, and the expressions of target proteins and mRNA were detected by Western blot and quantitative real time polymerase chain reaction (qRT-RCR), respectively.
The treatment with different doses of SMI reduced rat heart mass index and left ventricular mass index (P<0.05), significantly improved the left ventricular ejection fraction (P<0.05), decreased the levels of serum CK, LDH, cTnT, and NT-proBNP (P<0.05 or P<0.01), reduced the levels of serum sST2 and GDF-15 (P<0.05 or P<0.01), decreased the collagen volume fraction, reduced the expressions of rat myocardial type I and type III collagen (P<0.05 or P<0.01), and effectively alleviated myocardial fibrosis. And the study found that SMI promoted the expression levels of miR-30a and Bcl-2 in myocardium, and down-regulated the expression of Bax, which inhibited the activation of Caspase-3 and Caspase-9 (P<0.05 or P<0.01), and improved myocardial cell apoptosis.
SMI can alleviate myocardial injury and apoptosis caused by DOX, and its mechanism possibly by promoting the targeted expression of myocardial Bcl-2 protein through miR-30a.
探讨参麦注射液（SMI）抗阿霉素（DOX）诱导的心肌细胞凋亡的分子机制。
将40只无特定病原体（SPF）级雄性Sprague Dawley（SD）大鼠按随机数字表法分为5组，即对照组、模型组、miR - 30a激动剂组、参麦注射液低剂量（SMI - L）组和参麦注射液高剂量（SMI - H）组，每组8只。除对照组外，其余大鼠每周尾静脉注射DOX（2 mg/kg），连续4周以诱导心肌损伤，并给予不同方案连续干预2周。采用超声心动图检测心功能，用Van Gieson（VG）染色观察心肌病理变化。采用酶联免疫吸附测定（ELISA）法检测血清心肌损伤标志物，包括肌酸激酶（CK）、乳酸脱氢酶（LDH）、肌钙蛋白T（cTnT）、N末端脑钠肽前体（NT - proBNP）、可溶性ST2（sST2）和生长分化因子15（GDF - 15）。采用末端脱氧核苷酸转移酶介导的生物素化dUTP三磷酸尼克末端标记（TUNEL）法和透射电子显微镜观察心肌细胞凋亡情况，分别用蛋白质免疫印迹法（Western blot）和实时定量聚合酶链反应（qRT - RCR）检测靶蛋白和mRNA的表达。
不同剂量参麦注射液治疗可降低大鼠心脏质量指数和左心室质量指数（P<0.05），显著提高左心室射血分数（P<0.05），降低血清CK、LDH、cTnT和NT - proBNP水平（P<0.05或P<0.01），降低血清sST2和GDF - 15水平（P<0.05或P<0.01），降低胶原容积分数，降低大鼠心肌Ⅰ型和Ⅲ型胶原表达（P<0.05或P<0.01），有效减轻心肌纤维化。研究发现，参麦注射液可促进心肌中miR - 30a和Bcl - 2表达水平升高，下调Bax表达水平，抑制Caspase - 3和Caspase - 9激活（P<0.05或P<0.01），改善心肌细胞凋亡。
参麦注射液可减轻DOX所致心肌损伤及凋亡，其机制可能是通过miR - 30a促进心肌Bcl - 2蛋白的靶向表达。
