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Oxidative Medicine and Cellular Longevity
Volume 2019, Article ID 7976382, 12 pages
https://doi.org/10.1155/2019/7976382
Research Article

High Concentration of Low-Density Lipoprotein Results in Disturbances in Mitochondrial Transcription and Functionality in Endothelial Cells

1Heisenberg Group-Environmentally-Induced Cardiovascular Degeneration, IUF-Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
2Institute of Virology, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
3Core Unit Biosafety Level 2 Laboratory, IUF-Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
4Department of Anaesthesiology, HELIOS University Hospital Wuppertal, University of Witten/Herdecke, 42283 Wuppertal, Germany
5Heisenberg Group-Environmentally-Induced Cardiovascular Degeneration, Central Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany

Correspondence should be addressed to Judith Haendeler; ed.uhh@100eahuj

Received 24 January 2019; Revised 30 April 2019; Accepted 14 May 2019; Published 10 June 2019

Guest Editor: Valentina Giorgio

Copyright © 2019 Stefanie Gonnissen et al. 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.

Abstract

Concentrations of low-density lipoprotein (LDL) above 0.8 mg/ml have been associated with increased risk for cardiovascular diseases and impaired endothelial functionality. Here, we demonstrate that high concentrations of LDL (1 mg/ml) decreased NOS3 protein and RNA levels in primary human endothelial cells. In addition, RNA sequencing data, in particular splice site usage analysis, showed a shift in NOS3 exon-exon junction reads towards those specifically assigned to nonfunctional transcript isoforms further diminishing the functional NOS3 levels. The reduction in NOS3 was accompanied by decreased migratory capacity, which depends on intact mitochondria and ATP formation. In line with these findings, we also observed a reduced ATP content. While mitochondrial mass was unaffected by high LDL, we found an increase in mitochondrial DNA copy number and mitochondrial RNA transcripts but decreased expression of nuclear genes coding for respiratory chain proteins. Therefore, high LDL treatment most likely results in an imbalance between respiratory chain complex proteins encoded in the mitochondria and in the nucleus resulting in impaired respiratory chain function explaining the reduction in ATP content. In conclusion, high LDL treatment leads to a decrease in active NOS3 and dysregulation of mitochondrial transcription, which is entailed by reduced ATP content and migratory capacity and thus, impairment of endothelial cell functionality.