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Impaired endothelial cell-derived CX3CL1-mediated macrophage efferocytosis in hypertrophic cardiomyopathy based on
Yan Zhang1, Xin Yan2, Xiao-Lei Fu2
1Department of Anesthesiology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan Province, China.
Insights
Reduced CX3CL1 impairs macrophage efferocytosis, a key factor in hypertrophic cardiomyopathy (HCM) development. Enhancing CX3CL1 may offer a new therapeutic strategy for managing HCM progression.
Area of Science:
- Cardiovascular Biology
- Immunology
- Genetics
Background:
- Inflammatory proteins are linked to hypertrophic cardiomyopathy (HCM), but their exact role in disease development is unclear.
- Understanding these inflammatory pathways is crucial for identifying novel therapeutic targets for HCM.
Purpose of the Study:
- To investigate the role of inflammatory proteins, specifically CX3CL1, in the pathogenesis of hypertrophic cardiomyopathy (HCM).
- To explore the potential of targeting CX3CL1 for managing HCM progression.
Main Methods:
- Mendelian randomization (MR) analysis to assess the association between inflammatory proteins and HCM.
- Bioinformatics, in vivo, and in vitro models to elucidate the functional role of CX3CL1 in HCM.
- Analysis of CX3CL1 expression in cardiomyocytes and endothelial cells, and its association with macrophage efferocytosis.
Main Results:
- MR analysis revealed a negative correlation between CX3CL1 and HCM.
- CX3CL1 expression was significantly reduced in HCM, particularly in cardiomyocytes and endothelial cells, and further downregulated by angiotensin-II.
- CX3CL1 was strongly associated with macrophage efferocytosis, with decreased expression of efferocytosis markers (AXL, MERTK, TYRO3) in HCM, a process reversed by recombinant CX3CL1.
Conclusions:
- Impaired macrophage efferocytosis mediated by CX3CL1 is critical in the initiation and progression of HCM.
- Modulating CX3CL1 levels presents a potential therapeutic avenue for managing hypertrophic cardiomyopathy.
Background:
Clinical studies have demonstrated that multiple inflammatory related proteins are associated with hypertrophic cardiomyopathy (HCM). However, the precise role of these factors in the pathogenesis of HCM remains uncertain.
Methods:
The link between inflammatory related proteins and HCM was analyzed using Mendelian randomization (MR), followed by bioinformatics to explore the role of inflammatory related proteins in HCM. In vivo and in vitro models of HCM were established to elucidate how inflammatory related proteins influence HCM progression.
Results:
Our MR analysis revealed a negative correlation between the inflammation related protein CX3CL1 and HCM. Bioinformatics and in vivo data similarly demonstrated a reduction in CX3CL1 expression in HCM. CX3CL1 was found to be mainly expressed in cardiomyocytes and endothelial cells via the Human Protein Atlas database and its' expression in both cells was obviously downregulated after being treated by angiotensin-II. Importantly, functional characteristics and correlation analysis of CX3CL1 indicated that it was most closely associated with macrophages efferocytosis. Consequently, we examined the signature molecules (AXL, MERTK, and TYRO3) associated with efferocytosis, which revealed a significant decrease in their expression in HCM. Notably, recombinant mouse CX3CL1 (rm-CX3CL1) reversed this process.
Conclusions:
In conclusion, CX3CL1-meidated impaired efferocytosis plays a critical role in the initiation and development of HCM, and modulation of CX3CL1 may prove advantageous in managing HCM progression.
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