DAMPs exacerbate post-myocardial infarction cardiac injury via suppression of AP-1 signaling: critical role of impaired lymphatic endothelial cell proliferation

Background After myocardial infarction, impaired cardiac lymphatic drainage contributes to myocardial edema and inflammation, leading to irreversible heart damage. Early remodeling of the lymphatic network is essential to enhance lymphatic function and clear accumulated fluid and inflammatory cells. Purpose To explore the reasons for the temporal characteristics of lymphatic remodeling in the acute and chronic phases after myocardial infarction, and to promote the repair of the lymphatic network after myocardial infarction. Methods We employed temporal scRNA-seq of the heart following myocardial infarction, combined with pseudotime trajectory analysis, SCENIC transcription factor regulatory network reconstruction, and CellChat cell communication analysis to elucidate the mechanisms underlying differences in lymphatic endothelial cell proliferation. Lymphatic endothelial cells from the heart were sorted using flow cytometry to identify the expression of relevant proteins. The supernatant of cardiac homogenates collected at various time points post - myocardial infarction was used to simulate the cardiac microenvironment, revealing that DAMPs significantly influence lymphatic endothelial cell proliferation. We further established a DAMPs - deficient cell model by manipulating DAMP levels, thereby clarifying the role of DAMP inhibition in promoting cardiac lymphatic endothelial cell proliferation and accelerating cardiac lymphatic network remodeling after myocardial infarction. Results Our results showed significant temporal differences in the expression of AP - 1 complex - related genes in the heart during the acute and chronic phases following myocardial infarction. Specifically, overexpression of the AP - 1 complex and activation of its transcriptional signaling accelerated cardiac lymphatic network remodeling. Extracellular DAMP levels emerged as a crucial determinant of AP - 1 complex - related gene expression. In vitro experiments showed that manipulating DAMP levels directly affected the proliferation rate of lymphatic endothelial cells. In animal models, the use of DAMP - related molecular inhibitors not only increased lymphangiogenesis and promoted cardiac lymphatic network remodeling but also improved cardiac function post - myocardial infarction. Conclusion Our study demonstrates that DAMPs inhibit AP-1 signaling in cardiac lymphatic endothelial cells during the acute phase after myocardial infarction, reducing lymphatic endothelial cell proliferation and lymphangiogenesis. Inhibiting DAMPs can promote lymphatic endothelial cell proliferation, accelerate lymphatic network remodeling, and mitigate cardiac injury post - myocardial infarction.