Abstract 3001: Multiomics Analysis On Ascending Aorta Reveals New Potential Targets Of Marfan Syndrome-associated Thoracic Aortic Aneurysm

Abstract

Thoracic aortic aneurysm (TAA) is defined as the pathological enlargement of the first aortic trait. Patients with genetic Marfan syndrome (MFS) develop TAA in young age, since mutations of fibrillin-1 contribute to aortic wall detrimental weakening. To date, effective treatment options for this life-threatening condition are lacking, and pharmacological approaches are merely palliative, postponing the surgical aortic replacement. To identify new treatments for MFS-related TAA (MFS-TAA), current research is concentrated on pinpointing specific biological targets and mechanisms underlying this aortic disorder. Aim of this study is to unveil new specific and potential targets of MFS-TAA. Spatial transcriptomics was performed on healthy subject and MFS patients’ thoracic aortas, whereas protein expression levels of vascular smooth muscle cells from MFS patients’ (MFS-VSMC) and healthy subjects (HC-VSMC) were analyzed by quantitative mass spectrometry. -Omics results were validated by qRT-PCR and Western blot assays. Spatial transcriptomic results revealed 2 different cell clusters in the aortic tunicae , best representing aortic VSMC. Structural proteins ( e.g. , NES , DES , CNN1 ), were the most transcribed genes in MFS-TAA in comparison with HC aorta. Notably, proteomics yielded five proteins, statistically more abundant in MFS-VSMC vs. HC-VSMC (p<0.05): nestin, filamin B, A-kinase anchor protein 12, catenin delta-1, and heparan sulfate proteoglycan core protein. The Gene Ontology (GO) analysis performed on cellular components of both transcripts and proteins more expressed in MFS aortic samples highlighted the enrichment of GO terms related to extracellular compartment, actin and cytoskeleton components, and cell adhesion. We validated the levels of nestin, which increased expression in MFS specimens has been observed by both -omics techniques. The results of validation experiments confirmed higher nestin gene expression and protein levels in MFS-VSMC samples (p<0.05) when compared with HC-VSMC. Results suggest a valuable biological target role for nestin, which pharmacological targeting may represent, in the future, a novel and exploitable therapeutic option for limiting/inhibiting TAA onset or progression in MFS scenario.