Bioinformatic analysis of molecular mechanisms underlying the aortic valvular dysfunction in diabetes

Abstract

Aortic valve disease (AVD) and diabetes are global health issues in aging populations. Diabetes is not only a risk factor for AVD but also accelerates its progression, resulting in reduced prognosis and premature degeneration of aortic valves. Unfortunately, there are limited pharmacological treatments for AVD, and the costly and invasive valve replacement remains the main option. Thus, understanding the unique mechanisms linking AVD and diabetes is vital to develop new therapeutic strategies for prevention or delay of disease progression. Valvular endothelial cells (VECs) play a critical role in maintaining valve homeostasis and normal interactions with circulating blood cells. We hypothesize that the communication between monocytes and VECs in early diabetic conditions triggers phenotypic and molecular changes in both cell types, leading to altered endothelial integrity. RNA-seq analysis of VECs interacted for 2h with monocytes in high glucose (HG) revealed over 3000 DEGs (p-adj<0.05) associated with pathways like focal adhesion, tight junction, adherens junction, CAMs, regulation of actin cytoskeleton, ECM-receptor interaction, and leukocyte transendothelial migration. Further investigation demonstrated increased permeability and impaired adhesion of VECs to various ECM substrates under HG conditions. Transcriptome analysis of monocytes interacted with VECs in HG conditions showed activation of inflammatory pathways like TLR, NF-kB, JAK-STAT, and TNF signaling pathways, as well as increased expression of cell adhesion molecules and chemokines. These findings suggest that cellular interaction under diabetic conditions induces molecular changes, altering endothelial integrity and promoting an inflammatory profile of monocytes. Understanding these early mechanisms could help to discover new therapeutic targets suitable for the prevention or treatment of AVD in diabetic patients.