Molecular mechanisms of thoracic aortic aneurysm in Marfan Syndrome

Abstract

Background: Marfan Syndrome (MFS) is a monogenic multisystem disorder resulting from mutations in fibrillin-1, resulting in thoracic aortic aneurysm. Currently, effective treatments and a clear understanding of the underlying pathogenic mechanisms remain uncertain. This study sought evidence of pathway involvement in pathogenesis of MFS.

Methods: Comprehensive RNA-Seq, proteomics, miRNA, and DNA methylation studies were undertaken, using human aortic tissues from 15 MFS patients and 11 healthy controls. Subsequent pathway analysis and interrogation of related biological functions were performed.

Results: The transcriptomics and proteomics studies identified significant differential expression (DE) of multiple mRNA and proteins, allowing identification of potential pathogenic biological drivers such as inflammatory and oxidative stress responses. Furthermore, novel potential drivers, including mitochondrial dysfunction and mechanical stress responses, were also identified, associated with dysregulation in vascular smooth muscle cells, endothelial cells and the extracellular matrix in MFS pathogenesis. Significantly altered pathways included TGFβ, HIF-1, JAK-STAT, cGMP-PKG, sphingolipid, Rap1, and PI3K/AKT. Importantly, PI3K/AKT was identified as a common intermediate pathway with comprehensive crosstalk with all other pathways, highlighting the crucial role of PI3K/AKT signalling in MFS pathogenesis.

Furthermore, multi-omics analysis showed that the regulatory mechanisms controlling the DE of many RNA and proteins are regulated through epigenetic mechanisms. Investigation of DE miRNA and DNA methylation reinforced the signalling pathway findings of the driver mechanisms.

Conclusion: These findings provide new insights into underlying disease regulatory mechanisms and provide potential novel targets for therapeutic interventions in MFS.