iPSC-Derived Endothelial Cells Reveals LDLR-Dysfunction and Dysregulated Gene Expression Profiles in Familial Hypercholesterolemia

• DOI: 10.20944/preprints202311.0526.v1
• Publication Date: 2023-11-09T01:01:43Z
• Authors: Irina S. Zakharova; Alexander I. Shev...; MHD Amin Arssan; Alexei A Sleptcov; Maria S. Nazarenko; Aleksei A. Zarubin; Nina V. Zheltysheva; Vlada A. Shevchenko; Narek A. Tmoyan; Shoraan B. Saaya; Marat V. Ezhov; Valery V. Kukharchuk; Yelena V. Parfyonova; Suren M. Zakian
• Keywords: Endothelial Dysfunction

Defects in low-density lipoprotein receptor (LDLR) are associated with familial hypercholesterolemia (FH), manifested by atherosclerosis and cardiovascular disease. Defective LDLR hepatocytes leads to increased blood cholesterol level that damage vascular cells, especially endothelial through oxidative stress inflammation. However, the distinctions between cells from individuals normal defective not yet fully comprehended. In this study, we obtained examined derivatives of induced pluripotent stem (iPSC) generated previously conditionally healthy donors compound heterozygous FH patients carrying pathogenic alleles. iPSC-derived (iPSC-EC), detected protein predominantly its mature form, while iPSC-EC display reduced show abolished uptake. RNA-seq mutant revealed a unique transcriptome profile comprising downregulated genes related monocarboxylic acid transport, exocytosis cell adhesion, as well upregulated signaling pathways secretion leukocyte activation. Overall, these findings suggest defects increases susceptibility inflammation stress. This, combined elevated extrinsic levels, may result accelerated dysfunction, contributing early progression other pathologies FH.