Abstract Body: Congenital aortic valve stenosis (AVS) is a severe form of congenital heart disease (CHD), accounting for 3–6% of all CHD cases. It is characterized by malformation of the aortic valve, resulting in obstruction of the valve orifice. As congenital AVS is progressive, it ultimately impairs cardiac output, and without timely medical intervention, it can lead to heart failure and death. Current treatment options are limited to surgical interventions, which, due to the severity of the disease and associated risk factors, often require multiple procedures throughout a patient’s lifetime. Unfortunately, pharmacological therapies are not available, as the molecular mechanisms driving the disease are not well understood.
This study aims to identify clinically relevant biomarkers for assessing disease severity and to uncover novel pharmacological targets by dissecting the mechanisms underlying the development and progression of congenital AVS. We utilized a novel Notch1;Gata5 AVS mouse model developed in our lab to investigate changes in protein composition in the aortic valves. Proteomic analyses were conducted using HPLC-MS at postnatal day 10 (P10) of age to capture early stages of the disease. Our findings reveal significant changes in 364 proteins in Notch1;Gata5 compound mutants at P10. Pathway and Gene Ontology analyses revealed that many of these dysregulated proteins are associated with ECM assembly and organization pathways, consistent with the improper aortic valve remodeling observed in the AVS phenotype. Notably, the Notch1;Gata5 compound mutant valves exhibit altered protein abundance associated with Wnt and Integrin signaling pathways at P10 highlighting potential novel therapeutic targets for congenital AVS. In conclusion, our study explores the proteomic landscape of aortic valves in the Notch1;Gata5 AVS mouse model, identifying preliminary candidates that could inform future biomarker-based diagnostics and pharmacological interventions for congenital AVS.