Integrative bulk and single-cell transcriptomic analysis identifies a PLAUR-centered macrophage-associated programmed cell death signature in type A aortic dissection

Santrauka

Background Type A aortic dissection (TAAD) is a life-threatening aortic emergency characterized by inflammatory remodeling, extracellular matrix disruption, and programmed cell death (PCD). The cell-specific transcriptional features associated with immune activation and PCD-related aortic wall injury remain incompletely defined. This study investigated PCD-associated immune remodeling in TAAD and evaluated PLAUR as a macrophage-associated marker linked to these pathological changes. Methods Public bulk transcriptomic datasets were integrated with single-cell RNA sequencing, curated PCD-related gene sets, immune deconvolution, pathway enrichment, in silico perturbation analysis, and histological assessment of human aortic specimens. Results TAAD tissues exhibited marked transcriptomic alterations, with 2,217 genes meeting the exploratory differential-expression criteria, accompanied by increased PCD-related transcriptional activity. Single-cell analysis indicated that macrophage-enriched clusters showed relatively high PCD-related gene-set activity, while PLAUR transcripts were predominantly detected in macrophage-enriched clusters. PLAUR was upregulated in TAAD in both training and external validation datasets and strongly correlated with sample-level PCD scores. In the training dataset, PLAUR expression showed exploratory discrimination between TAAD and control tissue samples, with an AUC of 0.858. PLAUR-high samples showed enrichment of HIF-1, JAK-STAT, necroptosis, and apoptosis-related pathways. Immune deconvolution indicated relatively higher neutrophil- and M0 macrophage-associated signatures in TAAD, with PLAUR expression positively associated with myeloid-cell-related features. In silico perturbation analysis identified cytoskeletal and actin-related transcriptional changes associated with predicted PLAUR perturbation. Histological assessment demonstrated aortic wall disorganization, collagen remodeling, elastic fiber disruption, increased TUNEL positivity, and elevated PLAUR protein expression in TAAD lesions. Conclusions PLAUR is associated with macrophage-enriched inflammatory, proteolytic, and PCD-related remodeling in TAAD and may serve as a candidate marker of these pathological features. The present findings are associative and do not establish a causal role for PLAUR in aortic wall degeneration or dissection initiation. Spatially resolved and functional studies are required to determine whether PLAUR-positive macrophage states contribute mechanistically to TAAD pathogenesis.