Abstract 4364429: Decoding fibromyocytes' contributions to atherosclerosis: from senescence induction to promoting formation of the necrotic core

Background: Smooth muscle cells (SMC), an important cellular component of atherosclerosis, exhibit variant phenotypes after transdifferentiation. Their differentiation into fibromyocytes (FM) is regulated by the TCF21 transcription factor. The TCF21 gene was associated with decreased cardiovascular risk in a genome wide association study. However, RNA seq data suggesting a pro-inflammatory role of TCF21. Cell senescence is an irreversible cell proliferation arrest associated with vascular aging, and the progression of atherosclerosis. Hypothesis: We hypothesized that FM promote cellular senescence and exacerbate formation of the plaque’s necrotic core contributing to atherosclerotic plaque progression. Methods: We analyzed single-cell RNA seq (scRNAseq) datasets obtained for human coronary arteries, APOE-null mouse aortas, and a spatial transcriptomics (ST) dataset obtained for pig coronary artery. A senescence module score was calculated based on expression levels of 150+ senescence genes using a gene set enrichment algorithm. Spearman coefficients were calculated to align each gene expression pattern with senescence score distribution. Results: Gene expression profiling of atherosclerotic specimens obtained from humans, pigs and mice revealed that FM exhibited higher senescence module scores suggesting increased FM susceptibility to developing senescence. Cell type ratios were estimated for ST spots by deconvolution. FM was the most abundant cell type in the porcine coronary plaque’s fibrous cap (FC). Complement factor H (CFH) and versican (VCAN) were identified as top genes expressed in FM and highly correlated with senescence module scores: expression level of CFH and VCAN were 13 and 7.5-fold higher in FM compared to SMC, respectively. VCAN is highly expressed in senescent cells potentially promoting senescence of neighboring cells. CFH inhibits immune cell-mediated efferocytosis to clear dying cells, which may exacerbate formation of the necrotic core. Conclusions: Our results identified high levels of FM in FC in advanced coronary plaque and indicate that FM are prone to develop senescence. Upregulation of VCAN and CFH in FM are potential mechanisms promoting senescence and extension of the necrotic core. These findings revealed a novel role of FM in plaque progression and destabilization and identified FM as novel cellular target for development of anti-atherosclerotic therapy.