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Rheumatic heart disease (RHD) is responsible for nearly 250,000 deaths annually and poses a significant health threat in developing areas. The unclear pathogenesis of RHD makes the development of cost-effective treatments challenging, particularly as current surgical options are expensive and technologically demanding, exacerbating the economic and quality-of-life burdens for patients. Given the risks associated with direct human experimentation due to the uncertain pathogenesis, using a rat model infected with Group A Streptococcus (GAS) has become a crucial experimental strategy for RHD research. The development of an RHD rat model, refined over 23 years, now stands as a pivotal approach in studies aiming to understand the disease's pathogenesis. This review summarizes the evolution, characteristics, advantages, and limitations of the RHD rat model, offering insights into potential areas for improvement. It aims to provide researchers with a comprehensive understanding of the model, supporting the advancement of research methodologies and the discovery of innovative treatments for RHD., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Background: Rheumatic heart disease (RHD) is caused by inflammatory cells mistakenly attacking the heart valve due to Group A Streptococcus (GAS) infection, but it is still unclear which cells or genes are involved in the process of inflammatory cells infiltrating the valve. Inflammatory infiltration into the target tissue requires an increase in the expression of phosphorylated vascular endothelial-cadherin (p-VE-cad), p-VE-cad can increase the endothelial permeability and promote the migration of inflammatory cells across the endothelium. P-VE-cad is potentially regulated by RAS-related C3 botulinum substrate 1 (RAC1), together with phosphorylated proline-rich tyrosine kinase 2 (p-PYK2). While RAC1/p-PYK2/p-VE-cad is triggered by the activation of vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 is related to M1 macrophages adhering to the endothelium via very late antigen 4 (VLA4). Inflammatory infiltration into the valve is extremely important in the early pathogenesis of RHD. However, there is no relevant research on whether M1/VLA4/VCAM-1/RAC1/p-PYK2/p-VE-cad is involved in RHD; therefore, what we explored in this study was whether M1/VLA4/VCAM-1/RAC1/p-PYK2/p-VE-cad is involved., Methods: We established a rat model of RHD and a cell model of M1 macrophage and endothelial cell cocultivation. Subsequently, we measured the degree of inflammatory cell infiltration, the levels of IL-6/IL-17, the degree of fibrosis (COL3/1), and the expression levels of fibrosis markers (FSP1, COL1A1 and COL3A1) in the heart valves of RHD rats. Additionally, we detected the expression of M1/M2 macrophage biomarkers in rat model and cell model, as well as the expression of M1/VLA4/VCAM-1/RAC1/p-PYK2/p-VE-cad. We also tested the changes in endothelial permeability after coculturing M1 macrophages and endothelial cells., Results: Compared to those in the control group, the levels of inflammatory cell infiltration and fibrotic factors in the heart valves of RHD rats were significantly higher; the expression of M1 macrophage biomarkers (iNOS, CD86 and TNF-α) in RHD rats was significantly higher; and significantly higher than the expression of M2 macrophage biomarkers (Arg1 and TGF-β). And the expression levels of VLA4/VCAM-1 and RAC1/p-PYK2/p-VE-cad in the hearts of RHD rats were significantly higher. At the cellular level, after coculturing M1 macrophages with endothelial cells, the expression levels of VLA4/VCAM-1 and RAC1/p-PYK2/p-VE-cad were significantly higher, and the permeability of the endothelium was significantly greater due to cocultivation with M1 macrophages., Conclusions: All the results suggested that M1 macrophages and the VLA4/VCAM-1 pathway are potentially involved in the process of inflammatory infiltration in RHD., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Rheumatic heart disease (RHD) is frequently encountered in underdeveloped areas and primarily affects patients under the age of 40 years old. The pathogenesis of RHD has yet to be fully elucidated and surgical treatment remains the only option, which is expensive and technically demanding for patients in less developed areas. Signalling pathways are crucial for the occurrence and development of several diseases, and researchers worldwide have made progress in elucidating the signalling pathways associated with the pathogenesis of RHD. The aim of the present review was to discuss 6 signalling pathways implicated in the pathogenesis of RHD, summarize the methods and progress of these studies and propose future research directions. Important information on the pathogenesis of RHD according to the current progress of signalling pathway studies was also summarized, in the hope that this review may serve as a reference for future research on the signalling pathways involved in the pathogenesis of RHD., (Copyright: © Xian et al.)