Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Irina S. Zakharova
,
Alexander I. Shevchenko
,
MHD Amin Arssan
ORCID logo ,
Alexei A Sleptcov
ORCID logo ,
Maria S. Nazarenko
,
Aleksei A. Zarubin
,
Nina V. Zheltysheva
,
Vlada A. Shevchenko
,
Narek A. Tmoyan
ORCID logo ,
Shoraan B. Saaya
,
Marat V. Ezhov
ORCID logo ,
Valery V. Kukharchuk
,
Yelena V. Parfyonova
,
Suren M. Zakian
*
Version 1 : Received: 8 November 2023 / Approved: 8 November 2023 / Online: 8 November 2023 (16:14:59 CET)

A peer-reviewed article of this Preprint also exists.

Zakharova, I.S.; Shevchenko, A.I.; Arssan, M.A.; Sleptcov, A.A.; Nazarenko, M.S.; Zarubin, A.A.; Zheltysheva, N.V.; Shevchenko, V.A.; Tmoyan, N.A.; Saaya, S.B.; Ezhov, M.V.; Kukharchuk, V.V.; Parfyonova, Y.V.; Zakian, S.M. iPSC-Derived Endothelial Cells Reveal LDLR Dysfunction and Dysregulated Gene Expression Profiles in Familial Hypercholesterolemia. Int. J. Mol. Sci. 2024, 25, 689. Zakharova, I.S.; Shevchenko, A.I.; Arssan, M.A.; Sleptcov, A.A.; Nazarenko, M.S.; Zarubin, A.A.; Zheltysheva, N.V.; Shevchenko, V.A.; Tmoyan, N.A.; Saaya, S.B.; Ezhov, M.V.; Kukharchuk, V.V.; Parfyonova, Y.V.; Zakian, S.M. iPSC-Derived Endothelial Cells Reveal LDLR Dysfunction and Dysregulated Gene Expression Profiles in Familial Hypercholesterolemia. Int. J. Mol. Sci. 2024, 25, 689.

Abstract

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

Keywords

familial hypercholesterolemia; LDLR; patient-specific iPSCs; directed differentiation; endothelial cells

Subject

Biology and Life Sciences, Cell and Developmental Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Download PDF Download Supplementary

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0
Metrics 0
Get PDF Supplementary Files Cite Share 0
Bookmark BibSonomy Mendeley Reddit Delicious
×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.