The orphan receptor GPRC5B activates pro-inflammatory signaling in the vascular wall via Fyn and NFκB
Background and aims: Atherosclerosis is driven by an inflammatory process of the vascular wall. The novel orphan G-protein coupled receptor 5B of family C (GPRC5B) is involved in drosophila sugar and lipid metabolism as well as mice adipose tissue inflammation. Here, we investigated the role of GPRC...
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| Main Authors: | , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
12 February 2022
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| In: |
Biochemical and biophysical research communications
Year: 2022, Volume: 592, Pages: 60-66 |
| ISSN: | 1090-2104 |
| DOI: | 10.1016/j.bbrc.2022.01.009 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.bbrc.2022.01.009 Verlag, lizenzpflichtig, Volltext: https://linkinghub.elsevier.com/retrieve/pii/S0006291X22000171 
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| Author Notes: | Greta Verena Freundt, Friedrich Alexander von Samson-Himmelstjerna, Jan-Thorge Nitz, Mark Luedde, Johannes Waltenberger, Thomas Wieland, Norbert Frey, Michael Preusch, Hans-Joerg Hippe |
| Summary: | Background and aims: Atherosclerosis is driven by an inflammatory process of the vascular wall. The novel orphan G-protein coupled receptor 5B of family C (GPRC5B) is involved in drosophila sugar and lipid metabolism as well as mice adipose tissue inflammation. Here, we investigated the role of GPRC5B in the pro-atherogenic mechanisms of hyperglycemia and vascular inflammation. Methods: Immortalized and primary endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) were used for stimulation with high glucose or different cytokines. Adenoviral-or plasmid-driven GPRC5B overexpression and siRNA-mediated knockdown were performed in these cells to analyze functional and mechanistic pathways of GPRC5B. Results: In ECs and VSMCs, stimulation with high glucose, TNFa or LPS induced a significant upregulation of endogenous GPRC5B mRNA and protein levels. GPRC5B overexpression and knockdown increased and attenuated, respectively, the expression of the pro-inflammatory cytokines TNFa, IL-1b, IL-6 as well as the pro-atherogenic vascular adhesion molecules ICAM-1 and VCAM-1. Furthermore, the expression and activity of the metalloproteinase MMP-9, a component of atherosclerotic plaque stabilization, were significantly enhanced by GPRC5B overexpression. Mechanistically, GPRC5B increased the phosphorylation of ERK1/2 and activated NFkB through a direct interaction with the tyrosine kinase Fyn. Conclusions: Our findings demonstrate that GPRC5B is upregulated in response to high glucose and pro inflammatory signaling. GPRC5B functionally modulates the inflammatory activity in cells of the vascular wall, suggesting a pro-atherogenic GPRC5B-dependent positive feedback loop via Fyn and NFkB. Thus, GPRC5B warrants further attention as a novel pharmacological target for the treatment of vascular inflammation and possibly atherogenesis. (c) 2022 Elsevier Inc. All rights reserved. |
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| Item Description: | Online verfügbar: 7. Januar 2022, Artikelversion: 13. Januar 2022 Gesehen am 06.12.2022 |
| Physical Description: | Online Resource |
| ISSN: | 1090-2104 |
| DOI: | 10.1016/j.bbrc.2022.01.009 |