In recent years, the incidence of AMI has been on the rise, with very high mortality and disability rates, and has become one of the main causes of heart failure . The primary pathogenesis of acute myocardial infarction (AMI) is unstable, ruptured coronary atherosclerotic plaques, thrombotic formation of platelet aggregation, sustained coronary artery occlusion and myocardial cell ischaemia/anoxic necrosis. Myocardial necrosis after AMI triggers the local inflammatory response and activates the immune system. Myocardial infarction not only directly leads to myocardial necrosis, but the secondary inflammatory immune response can also seriously damage cardiac function and can cause heart failure and various arrhythmias [4, 27-29].
As acquired immune cells, B cells secrete cytokines such as transforming growth factor-β1 (TGF-β1), tumour necrosis factor-α (TNF-α), interleukin-1β (IL-β1), and interleukin-6 (IL-6), which promote fibrosis progression. A large number of studies have shown that cytokines are involved in the inflammatory response and the fibrosis process of kidney, liver and lung tissues [30, 31]. In recent years, there have been reports on the involvement of B cells in the myocardial fibrosis process of cardiovascular diseases, but the mechanism of action of B cells and their cytokines in the myocardial infarction process after AMI is still unclear. Therefore, our study intended to establish a mouse AMI model by ligating the LAD artery of C57BL/6 mice to observe the changes in activated B cells and cytokines at different time points and the relationship between them. The study of an animal myocardial infarction model can help to explore its mechanism and treatment. Cardiovascular genes in mice are highly similar to those in humans , and current gene knockout and other gene technologies are achieved in mice. However, due to their small size, poor tolerance, and lack of convenience for surgery and operations, mouse myocardial infarction modelling has high requirements, often after a certain period of training to master the mouse AMI modelling technology. Ligation of the LAD artery is the mainstream method for the production of AMI models in mice , which requires a series of processes such as management of anaesthesia, endotracheal intubation, ventilator-assisted breathing, thoracotomy, pre-exposure of the descending branch, pre-ligation of the descending branch, chest closure, resuscitation, removal of the ventilator and so on.
In a study of patients with heart failure after myocardial infarction and various reasons, it was found that various anti-myocardial antibodies exist in myocardial tissue. Endothelial cells are damaged after myocardial ischaemia and hypoxia, secreting various cytokines, such as chemokines and inflammatory mediator factors. The ischaemic necrosis of the myocardium exposes new antigens, which trigger the immune response, antibody action and immune cell infiltration . Moreover, the congenital immune system plays an important role in the myocardial fibrosis process. Neutrophils are first released due to damaged endothelial cells, and chemokines, growth factors and chemical signals affect the damaged myocardium. Then, natural killer cells, dendritic cells, mononuclear macrophages infiltrate into the damaged heart tissue, secreting cytokines and releasing oxygen free radicals, causing acute inflammation, and increasing infiltration of T cells and B cells into damaged areas. By secreting cytokines, producing antibodies and presenting antigens, B cells further aggravate myocardial injury under the combined action of inflammatory cytokines secreted by various activated immune cells [35-37]. In addition, B cells not only damage the myocardium but are also related to myocardial fibrosis after myocardial injury. In the B cell-deficient mouse cardiomyopathy model, it was found that with the decrease in TNF-α, serum collagen I and III levels decreased, and the amount of collagen fibres deposited in the extracellular matrix decreased . Thus, it can be inferred that B cells have the role of promoting myocardial fibrosis. Zouggari et al. found that myocardial B cells expressed Ccl7, a chemokine recruited to myocardial infiltration by CCR2 receptor-mediated monocytes, which could lead to myocardial damage. After injection of anti-CD20 antibody, monocyte infiltration was reduced, and myocardial damage was alleviated . However, Goodchild et al. reported that intramyocardial injection of bone marrow-derived B lymphocytes into SD rats with myocardial infarction is beneficial to cardiac function because it reduced in situ cell apoptosis and helped maintain the ejection fraction . The two studies drew different conclusions about B cells because Goodchild et al. used immature B cells, while Zouggari et al. used anti-CD20 antibodies to exhaust mature B cells.
In our study, BKO mice were used to investigate the effect of B-cell deletion on myocardial collagen deposition after AMI. The results showed that B-cell deletion reduced the expression of the cytokines TNF-α, IL-1β, IL-6, and TGF-1β, decreased myocardial collagen synthesis after AMI, alleviated myocardial fibrosis, improved left ventricular remodelling, and maintained the left ventricular ejection fraction. The BKO mice used in this study completely lacked the entire B-cell system, and the B cells were removed from the source, which is different from the elimination of B cells by drug depletion, including anti-CD20, anti-CD22, anti-BAFF and other antigens that exhaust the blood circulation and express corresponding antigens. B-cell factors could be completely excluded.