Dysregulated lncRNAs are associated with the progressive arterial phenotype in Hutchinson–Gilford Progeria Syndrome

Abstract

Hutchinson–Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by de novo LMNA mutations. Patients develop severe systemic symptoms limiting life quality and ultimately causing death from cardiovascular events. Despite extensive research, treatment options remain limited. Here, we investigated the role of long non-coding RNAs (lncRNAs) in the development of vascular pathology in HGPS. We analyzed an available single-cell RNA sequencing dataset from aortic arch cells of wild-type and LmnaG609G/G609G mice aged 6, 10 and 12 weeks. Several lncRNAs implicated in cardiovascular disease, such as Carmn, Dancr, Gas5, Kcnq1ot1, Meg3, Neat1, Pvt1, or Trp53cor1, were dysregulated in LmnaG609G/G609G vascular smooth muscle cells (VSMCs). This dysregulation was most pronounced in disease-enriched VSMCs, which showed severe dysfunction with disease progression. Furthermore, lncRNA changes were dynamic over time. Transcription factor motif enrichment analysis identified putative regulatory links between dysregulated lncRNAs, and cellular programs associated with VSMC stress responses and phenotypic switching. In contrast, LmnaG609G/G609G fibroblasts displayed a distinct lncRNA expression profile, including H19, Gas5, Kcnq1ot1, and Pvt1, associated with fibrosis and inflammation. Together, our findings reveal progressive, and cell type–specific lncRNA dysregulation in the HGPS vasculature and highlight lncRNAs as candidates for exploring new therapeutic strategies. Graphical Abstract