Connecting the Dots: Molecular Pathways in Bicuspid Aortopathy Explored

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Junta de Andalucía, Ministerio de Ciencia e Innovación Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation. It predisposes to thoracic aortic dilatation (TAD), aneurysm and dissection. The current consensus is that the genetic defect that leads to the aortic valve malformation also causes structural anomalies of the ascending aorta. Altered hemodynamics caused by the abnormal valve morphology would accelerate aortic media degeneration. Molecular markers and pathways involved in the aetiology and pathophysiology of bicuspid aortopathy are poorly understood. To elucidate the molecular and cellular mechanisms of the disease and to identify potential predictive molecular markers using a well-established isogenic hamster model (T strain) with a high (∼40%) incidence of BAV TAD. Comparative quantitative proteomics combined with Western blot and morpho-molecular analyses in the ascending aorta of tricuspid aortic valve (TAV) and BAV animals from the T strain and TAV animals from a control strain. This strategy allows exploring independently the genetic and hemodynamic effects on the aorta in genetically homogeneous populations. The major molecular defect in the aorta of genetically homogeneous BAV individuals is PI3K/AKT overactivation caused by alterations in the EGF, ANGII and TGF-β signalling pathways. PI3K/AKT affects the downstream eNOS, MAP2K1/2, NF-κB, mTOR and WNT pathways. Most of these alterations are seen in independent patient studies with different clinical presentations, but not in TAV hamsters from the T strain, which mainly show downregulation of the WNT pathway. We identify a combination of defective interconnected molecular pathways, directly linked to the central PI3K/AKT pathway, common to both BAV-associated TAD patients and hamsters. The defects indicate a shift of smooth muscle cells towards the synthetic phenotype induced by endothelial-to-mesenchymal transition, oxidative stress and inflammation. WNT signalling represents a genetic factor that may cause aortic structural abnormalities and aneurysm predisposition, whereas hemodynamics is the main trigger of molecular changes, likely determining the progression of aortopathy. We identify twenty-seven novel potential biomarkers with high predictive value.