Abstract Body: Introduction: Aortic dissection (AD) is a life-threatening cardiovascular emergency with an extremely high mortality rate. Hypertension is recognized as a major risk factor for AD, but the molecular mechanisms beyond hemodynamic alterations remain incompletely understood. Trained immunity, driven by epigenetic reprogramming, enables innate immune cells to mount rapid and intense immune responses upon recurrent stimulation, thereby aggravating inflammation.
Hypothesis: Hypertension induces monocyte trained immunity via histone modification. Monocytes differentiate into MHCII⁺ macrophages within the aortic wall; following hypertensive stimulation, these MHCII⁺ macrophages promote AD formation, intensify the inflammatory microenvironment, and exacerbate AD progression.
Methods: Multi-omics integrating clinical laboratory results and single-cell transcriptomic profiling were used to identify the primarily attributable cell type in hypertensive AD. Bone marrow transplantation of mice were used to observe whether the hypertensive myeloid cells could worsen AD. Transcriptomic analyses from human and mouse samples, combined with ATAC-seq data, were used to analyze chromatin accessibility and gene expression changes.
Results: Differences in the hypertensive aorta are primarily attributable to alterations in the monocyte–macrophage lineage. Bone marrow transplantation from hypertensive mice indicated that myeloid cell function is modulated by hypertension, worsening both the incidence and severity of AD. Transcriptomic and ATAC-seq data revealed marked alterations in chromatin accessibility within the MHCII⁺ macrophage subset under hypertensive conditions, notably with significant upregulation of H3K4me3 regulatory enzymes.
Conclusions: Hypertension induces monocyte trained immunity, potentially via H3K4me3 modification, leading to increased differentiation of monocytes into MHCII⁺ macrophages in aorta. These macrophages, under hypertensive stimulation, contribute to the formation and progression of AD by exacerbating inflammatory microenvironment.