Recombinant human thymosin beta 4 improves ischemic cardiac dysfunction in mice and patients with acute ST-segment elevation myocardial infarction after reperfusion
Abstract
Aims: Despite advancements in primary percutaneous coronary intervention (PCI), cardiac dysfunction remains a challenge in patients with ST-segment elevation myocardial infarction (STEMI). Although thymosin beta 4 has shown cardioprotective effects in preclinical MI models, its impact on chronic cardiac functional recovery post ischemia/reperfusion (I/R), especially in STEMI, warrants further investigation. This study aims to explore the therapeutic potential of recombinant human thymosin beta 4 (rhTB4) in both murine models subjected to I/R and in subjects with STEMI post-PCI.
Methods And Results: In C57BL/6J mice, 7-day rhTB4 treatment prevented cardiac dysfunction and fibrosis 28 days post-I/R surgery and significantly reduced plasma NT-proBNP levels at both 1 day and 28 days post-I/R. Similarly, in a permanent ligation model, rhTB4 improved cardiac function and reduced infarct size at 8 weeks post-MI. RNA-seq analysis of I/R heart tissues revealed that rhTB4 modulated the ErbB signaling pathway. In vitro hypoxia/reoxygenation (H/R) models (HL-1, neonatal mouse cardiomyocytes, H9C2) demonstrated that rhTB4 activated the ErbB2/Raf1 signaling pathway, attenuated cardiomyocyte apoptosis and suppressed pro-apoptotic protein Bad expression. The cardioprotective effects of rhTB4 on cardiac function and adverse cardiac remodeling in I/R mice were abolished by ErbB2 inhibition. In a randomized, placebo-controlled, double-blind trial involving 96 STEMI patients, the infarcted areas were significantly reduced in the rhTB4 group, which received the first dose of rhTB4 within 8 h after PCI (n = 43), as compared to the placebo group at the 90-day follow-up. However, the overall differences in infarcted areas were not significantly between the rhTB4 group and the placebo group (n = 96).
Conclusion: These findings underscore the crucial role of rhTB4 in mitigating cardiac dysfunction in an ErbB2-dependent manner. The clinical relevance of rhTB4 is demonstrated through a randomized controlled trial, emphasizing its translational potential. Further rigorous randomized studies are needed to assess the significance of early rhTB4 use post-myocardial infarction reperfusion.
Authors: Yuze Zhang, Qiuting Dong, Xiaohui Bian, Zheng Qiao, Chuanjue Cui, Ning Yang, Jincan Liu, Rui Fu, Jun Zhang, Lei Jia, Chao Wu, Jincheng Guo, Wenhua Lin, Jingping Wang, Jiamao Fan, Yang Li, Fan Liu, Bin Yang, Xinwei Jia, Chuanyu Gao, Ming Bai, Yi He, Chengquan Han, Dong Yin, Kefei Dou
Journal: Cardiovascular research
DOI: 10.1093/cvr/cvaf223