Histone lactylation-induced GLI3 activation drives macrophage M1 polarization and exosomal SERPINE1 release in abdominal aortic aneurysm progression

Abstract M1 macrophages promote the progression of abdominal aortic aneurysm (AAA). Lactate-mediated histone lactylation modification regulates macrophage M1 polarization. However, the role and molecular mechanisms of lactylation-mediated macrophage M1 polarization in AAA remain unclear. Histone lactylation in macrophages was investigated using clinical specimens and AAA animal models, with subsequent validation at the cellular level. Key genes undergoing lactylation modification were screened through RNA-seq and CUT&Tag joint analysis. Functional validation was conducted to demonstrate that the target genes mediate AAA progression by regulating macrophage M1 polarization and subsequent exosome-mediated endothelial dysfunction. We observed elevated serum lactate levels in AAA patients. H3K18 lactylation (H3K18la) and M1 macrophage marker CD86 were upregulated and co-localized in the aortic aneurysm of AAA mice. Lactate upregulated H3K18la levels and M1 polarization markers CD80, MCP-1, and iNOS, while downregulating M2 polarization marker CD206. Transcriptome sequencing identified 305 genes that were abnormally expressed in lactate-treated macrophages. A total of 839 differentially modified lactylation peaks were identified in lactate-treated macrophages, with 195 peaks enhanced and 644 peaks weakened. Notably, GLI3 was identified as a highly lactylated gene, and its knockdown significantly suppressed macrophage M1 polarization. Lactate induced macrophage M1 polarization by promoting GLI3 expression. Furthermore, lactate-polarized M1 macrophages induced endothelial dysfunction by secreting the exosomal protein SERPINE1. This study demonstrates that histone lactylation-mediated GLI3 activation drives macrophage M1 polarization and subsequent secretion of exosomal SERPINE1, inducing endothelial dysfunction in AAA progression. This study provides significant advances in our comprehensive understanding of AAA pathogenesis mediated by endothelial dysfunction.