Taskinen, Juuso H. and Ruhanen, Hanna and Matysik, Silke and Olkkonen, Vesa M. (2023) Systemwide effects of ER-intracellular membrane contact site disturbance in primary endothelial cells. JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 232: 106349. ISSN 0960-0760, 1879-1220
Full text not available from this repository. (Request a copy)Abstract
Membrane contact sites (MCS) make up a crucial route of inter-organelle non-vesicular transport within the cell. Multiple proteins are involved in this process, which includes the ER-resident proteins vesicle associated membrane protein associated protein A and -B (VAPA/B) that form MCS between the ER and other membrane compartments. Currently most functional data on VAP depleted phenotypes have shown alterations in lipid homeostasis, induction of ER stress, dysfunction of UPR and autophagy, as well as neurodegeneration. Literature on concurrent silencing of VAPA/B is still sparse; therefore, we investigated how it affects the macromolecule pools of primary endothelial cells. Our transcriptomics results showed significant upregulation in genes related to inflammation, ER and Golgi dysfunction, ER stress, cell adhesion, as well as Coat Protein Complex-I and -II (COPI, COP-II) vesicle transport. Genes related to cellular division were downregulated, as well as key genes of lipid and sterol biosynthesis. Lipidomics analyses revealed reductions in cholesteryl esters, very long chain highly unsaturated and saturated lipids, whereas increases in free cholesterol and relatively short chain unsaturated lipids were evident. Furthermore, the knockdown resulted in an inhibition of angiogenesis in vitro. We speculate that ER MCS depletion has led to multifaceted outcomes, which include elevated ER free cholesterol content and ER stress, alterations in lipid metabolism, ER-Golgi function and vesicle transport, which have led to a reduction in angiogenesis. The silencing also induced an inflammatory response, consistent with upregulation of markers of early atherogenesis. To conclude, ER MCS mediated by VAPA/B play a crucial role in maintaining cholesterol traffic and sustain normal endothelial functions.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | INTERCELLULAR-ADHESION MOLECULE-1; BINDING CASSETTE TRANSPORTER; POLYUNSATURATED FATTY-ACIDS; ENDOPLASMIC-RETICULUM; NEUROTROPHIC FACTOR; CHOLESTEROL EFFLUX; PROGENITOR CELLS; VAPB INTERACTS; E-SELECTIN; IN-VITRO; Transcriptomics; Lipidomics; Inflammation; Endothelial cells; Cholesterol; VAPA and VAPB |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 31 Jan 2024 12:38 |
| Last Modified: | 31 Jan 2024 12:38 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60567 |
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