Abstract P113: Multi Omics Analysis Identified Fndc1 And Mxra5 As Novel Extracellular Matrix Proteins In Aortic Stenosis

Abstract

Calcified aortic valve disease (CAVD) affects over six million Americans and is associated with changes in valve leaflets' mechanical properties, resulting in impaired valvular blood flow. Currently, there is no viable pharmacological treatment to stop the disease's progression or activate mineral regression. The only effective therapy to treat CAVD is aortic valve replacement (AVR) or transcatherization (TAVR). Therefore, it is imperative to understand the molecular mechanisms leading to aortic valve mineralization to identify new pharmacological targets. In this work, we examined the expression of extracellular matrix proteins (ECM) during valve calcification. Method: We used both RNAseq (n=18) and Proteomics (n=15) on explanted human valves of two different human cohorts to study the modulation of ECM proteins. Proteins were isolated from the fibrotic and the calcific side of each valve tissue. We next confirm our data in isolated human valve cells. Cells were treated with calcifying medium for one week and secreted ECM proteins were analyzed at different time points: Baseline, 3 days, and 7 days. Results: our network analysis revealed an interaction between ECM, metabolic, complement, and lipids transporters proteins. We identified SPP1, VTN, THSB2, MATN2, FNDC1, and MXRA5 as the common modulated ECM protein in both RNAseq and proteomics data set. Conclusion: This study yields new insight into ECM proteins expression during the aortic valve calcification process, and identified two new ECM proteins, MXRA5 and FNDC1, in aortic stenosis. The disruption of ECM proteins was more significant in the calcified stage and it was accompanied by a down-regulation of many metabolic enzymes.