Atherosclerosis is driven by chronic inflammation of the vascular wall, in which macrophages play a central role. The orphan G protein-coupled receptor GPRC5B is expressed in vascular cells and macrop Show more
Atherosclerosis is driven by chronic inflammation of the vascular wall, in which macrophages play a central role. The orphan G protein-coupled receptor GPRC5B is expressed in vascular cells and macrophages and is upregulated during monocyte-to-macrophage differentiation. It has been shown to activate NFκB-dependent inflammatory pathways in adipose tissue and glomeruli. Here, we investigated the impact of GPRC5B on macrophage infiltration and the progression of atherosclerotic plaque development in vivo. Bone marrow from heterozygous GPRC5B-transgenic C57BL/6 mice and wild-type controls was transplanted into lethally irradiated LDL receptor-deficient mice. Animals were fed a Western-type diet for 16 weeks, after which atherosclerotic lesions in the aortic sinus were analyzed. Mice receiving GPRC5B-transgenic bone marrow showed no significant differences in serum lipids or cardiac mass indices. However, they exhibited significantly increased macrophage infiltration within atherosclerotic plaques and a non-significant trend toward larger and more complex lesions. GPRC5B overexpression in bone marrow-derived monocyte/macrophage lineage cells promotes a more inflammatory plaque phenotype, characterized by enhanced macrophage infiltration. These findings highlight GPRC5B as a potential modulator of plaque progression and suggest it may represent a novel therapeutic target in vascular inflammation and atherosclerosis. Show less
Inflammation is a major driver of cardiac remodeling. Cardiac fibroblasts play an integral role in cardiac inflammation, fibrosis and remodeling. The orphan G-protein-coupled-receptor 5B of family C ( Show more
Inflammation is a major driver of cardiac remodeling. Cardiac fibroblasts play an integral role in cardiac inflammation, fibrosis and remodeling. The orphan G-protein-coupled-receptor 5B of family C (GPRC5B) has recently been shown to have pro-inflammatory effects in adipocytes via the NFκB-signaling-pathway. Here, we investigated whether GPRC5B is involved in myocardial inflammation and fibrosis. Using neonatal rat cardiac fibroblasts (NRCF) we show that the transcription and the expression of endogenous GPRC5B is induced by stimulation with TNFα and LPS as well as through cyclic mechanical stretch, while the principle pro-fibrotic factor TGFβ has no effect on the GPRC5B expression. Furthermore, we demonstrate that adenoviral overexpression and siRNA-mediated knockdown of GPRC5B in NRCF significantly alters the transcription level of the pro-inflammatory and pro-fibrotic cytokines TNFα, IL-1β, IL-6 and MCP-1, and extracellular matrix-degrading MMP-9 in vitro. Additionally, in adult GPRC5B-transgenic mice the protein expression of collagen-1A1 is decreased and the production of MMP-9 is increased, indicating remodeling of the extracellular matrix in vivo. Our data show that GPRC5B is up-regulated by inflammatory signals and mechanical stress in NRCF, while GPRC5B modulates the inflammatory response of cardiac fibroblasts and the degradation of extracellular matrix-proteins in the mice heart. Thus, our findings are the first to report a novel role of the orphan receptor GPRC5B in fibroblast-driven myocardial inflammation and cardiac remodeling. Show less