Transcriptional Profiling of Normal, Stenotic, and Regurgitant Human Aortic Valves

The genetic mechanisms underlying aortic stenosis (AS) and aortic insufficiency (AI) disease progression remain unclear. We hypothesized that normal aortic valves and those with AS or AI all exhibit unique transcriptional profiles. Normal control (NC) aortic valves were collected from non-matched donor hearts that were otherwise acceptable for transplantation (n= 5). Valves with AS or AI (n= 5, each) were collected from patients undergoing surgical aortic valve replacement. High-throughput sequencing of total RNA revealed 6438 differentially expressed genes (DEGs) for AS vs. NC, 4994 DEGs for AI vs. NC, and 2771 DEGs for AS vs. AI. Among 21 DEGs of interest,APCDD1L,CDH6,COL10A1,HBB,IBSP,KRT14,PLEKHS1,PRSS35, andTDO2were upregulated in both AS and AI compared to NC, whereasALDH1L1,EPHB1,GPX3,HIF3A, andKCNT1were downregulated in both AS and AI (p< 0.05).COL11A1,H19,HIF1A,KCNJ6,PRND, andSPP1were upregulated only in AS, andNPYwas downregulated only in AS (p< 0.05). The functional network for AS clustered around ion regulation, immune regulation, and lipid homeostasis, and that for AI clustered around ERK1/2 regulation. Overall, we report transcriptional profiling data for normal human aortic valves from non-matched donor hearts that were acceptable for transplantation and demonstrated that valves with AS and AI possess unique genetic signatures. These data create a roadmap for the development of novel therapeutics to treat AS and AI.