Multi-Omics Profiling in Marfan Syndrome: Further Insights into the Molecular Mechanisms Involved in Aortic Disease

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Thoracic aortic aneurysm is a potentially life-threatening disease with a strong genetic contribution. Despite identification of multiple genes involved in aneurysm formation, little is known about the specific underlying mechanisms that drive the pathological changes in the aortic wall. The aim of our study was to unravel the molecular mechanisms underlying aneurysm formation in Marfan syndrome (MFS). We collected aortic wall samples from FBN1 variant-positive MFS patients (n = 6) and healthy donor hearts (n = 5). Messenger RNA (mRNA) expression levels were measured by RNA sequencing and compared between MFS patients and controls, and between haploinsufficient (HI) and dominant negative (DN) FBN1 variants. Immunohistochemical staining, proteomics and cellular respiration experiments were used to confirm our findings. FBN1 mRNA expression levels were highly variable in MFS patients and did not significantly differ from controls. Moreover, we did not identify a distinctive TGF-β gene expression signature in MFS patients. On the contrary, differential gene and protein expression analysis, as well as vascular smooth muscle cell respiration measurements, pointed toward inflammation and mitochondrial dysfunction. Our findings confirm that inflammatory and mitochondrial pathways play important roles in the pathophysiological processes underlying MFS-related aortic disease, providing new therapeutic options.

Original languageEnglish
Article number438
JournalInternational Journal of Molecular Sciences
Issue number1
Early online date31 Dec 2021
Publication statusPublished - Jan 2022

Bibliographical note

Funding: This work was supported by funding from the Dutch Heart Foundation (03-003-2014-T007)
and an Erasmus University Rotterdam Fellowship to Ingrid M. B. H. van de Laar, and funding from
Stichting Lijf en Leven (Genexpressie analyse ter detectie van de moleculaire mechanismen van
aneurysmavorming-GAMMA) to Jeroen Essers and Ingrid van der Pluijm.


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