The orphan receptor GPRC5B activates pro-inflammatory signaling in the vascular wall via Fyn and NFκB

• Verfasst von: Freundt, Greta [VerfasserIn]
• Verfasst von: Samson-Himmelstjerna, Friedrich Alexander von [VerfasserIn]
• Verfasst von: Nitz, Jan-Thorge [VerfasserIn]
• Verfasst von: Lüdde, Mark [VerfasserIn]
• Verfasst von: Waltenberger, Johannes [VerfasserIn]
• Verfasst von: Wieland, Thomas [VerfasserIn]
• Verfasst von: Frey, Norbert [VerfasserIn]
• Verfasst von: Preusch, Michael [VerfasserIn]
• Verfasst von: Hippe, Hans-Jörg [VerfasserIn]
• Titel: The orphan receptor GPRC5B activates pro-inflammatory signaling in the vascular wall via Fyn and NFκB
• Verf.angabe: Greta Verena Freundt, Friedrich Alexander von Samson-Himmelstjerna, Jan-Thorge Nitz, Mark Luedde, Johannes Waltenberger, Thomas Wieland, Norbert Frey, Michael Preusch, Hans-Joerg Hippe
• E-Jahr: 2022
• Jahr: 12 February 2022
• Umfang: 7 S.
• Fussnoten: Online verfügbar: 7. Januar 2022, Artikelversion: 13. Januar 2022 ; Gesehen am 06.12.2022
• Titel Quelle: Enthalten in: Biochemical and biophysical research communications
• Ort Quelle: [Amsterdam] : Elsevier B.V., 1959
• Jahr Quelle: 2022
• Band/Heft Quelle: 592(2022), Seite 60-66
• ISSN Quelle: 1090-2104
• DOI: doi:10.1016/j.bbrc.2022.01.009
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Atherosclerosis
• Sach-SW: cells
• Sach-SW: gpcr
• Sach-SW: gprc5b
• Sach-SW: high glucose
• Sach-SW: Hyperglycemia
• Sach-SW: protein-coupled receptor
• Sach-SW: transduction
• Sach-SW: Vascular inflammation
• K10plus-PPN: 1824515278

Abstract

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.