Protective role of Tongxinluo in mitigating myocardial fibrosis in mice with acute myocardial infarction via neuregulin-1 upregulation and Inhibition of endothelium-interstitial transition

Abstract

Acute myocardial infarction (AMI) is a leading cause of heart failure, often accompanied by myocardial fibrosis (MF), characterized by excessive extracellular matrix accumulation. Endothelial-to-mesenchymal transition (EndMT) plays a key role in MF progression post-AMI. Neuregulin-1 (NRG-1), a growth factor with cardioprotective properties, has emerged as a potential therapeutic target. Tongxinluo (TXL), a traditional Chinese medicine, mitigates MF by upregulating NRG-1. This study elucidates the mechanisms underlying the protective effects of NRG-1 and TXL against MF following AMI. Left anterior descending artery ligation established a model for mice with AMI. Adeno-associated virus was used to modulate NRG-1 expression in the myocardium. Echocardiography assessed cardiac function, and histological staining was used to evaluate MF. Expression levels of markers for myofibroblasts (α-SMA, FSP-1) and endothelial cells (CD31, VE-cadherin) were analysed to investigate EndMT. The involvement of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway in NRG-1’s protective mechanism was validated using biochemical methods. Tongxinluo was administered to mice with AMI via gavage for 4 weeks, and its effects on cardiac function, MF and EndMT were assessed. Overexpression of NRG-1 in mice with AMI ameliorated cardiac dysfunction and reduced interstitial and perivascular fibrosis, whereas NRG-1 deficiency exacerbated these effects. NRG-1 protected against EndMT, as evidenced by changes in myofibroblast and endothelial cell markers. The PI3K/AKT signalling pathway was involved in NRG-1’s protective mechanism against MF. The administration of TXL to mice with AMI improved cardiac function and reduced MF by activating NRG-1. Furthermore, TXL inhibited EndMT post-AMI through the NRG-1/PI3K/AKT pathway. NRG-1 and TXL protect against MF post-AMI by mitigating EndMT through the PI3K/AKT pathway. These findings suggest that targeting NRG-1 or using TXL may be promising therapeutic strategies for MF following AMI.