Abstract
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.
Highlights
Thoracic aortic aneurysms most commonly involve the aortic root and/or proximal ascending aorta and are often discovered incidentally
We studied the expression of several members of the TGF-β pathway, including TGFβ1, phosphorylated SMAD2, and connective tissue growth factor (CTGF), by immunohistochemistry in the wall of the proximal ascending aorta of Marfan syndrome (MFS) patients and controls
In aortic samples from MFS patients, we identified a gene expression signature indicative of inflammation and mitochondrial dysfunction
Summary
Thoracic aortic aneurysms most commonly involve the aortic root and/or proximal ascending aorta and are often discovered incidentally. If left untreated, thoracic aortic aneurysms can result in aortic dissection, rupture or sudden death. 20% of individuals with thoracic aortic aneurysms and dissections have affected family members, suggesting a genetic predisposition [1]. This is referred to as heritable thoracic aortic disease (HTAD) [2]. Patients with MFS typically present with aortic root dilatation, ectopia lentis and skeletal features. A pathogenic variant in FBN1 can be identified in over 90% of patients that fulfill the Ghent criteria for MFS [4,5]
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