Role for CaMKII inhibition in rheumatoid arthritis: effects on HIF-1-induced VEGF production by rheumatoid synovial fibroblasts

• Published in: Annals of the New York Academy of Sciences 2009-09, Vol.1173 (1), p.706-711
• Main Authors: Westra, Johanna, Brouwer, Elisabeth, Bouwman, Erwin, Doornbos-van der Meer, Berber, Posthumus, Marcel D, van Leeuwen, Miek A, Limburg, Pieter C, Ueda, Yutaka, Kallenberg, Cees G M
• Format: Article
• Language: English
• Subjects: Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Benzylamines - pharmacology; Blotting, Western; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell Hypoxia; Cells, Cultured; Chromones - pharmacology; Enzyme-Linked Immunosorbent Assay; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Flavonoids - pharmacology; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Interleukin-1beta - pharmacology; Interleukin-6 - genetics; Interleukin-6 - metabolism; Morpholines - pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinase Inhibitors - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sulfonamides - pharmacology; Synovial Membrane - drug effects; Synovial Membrane - metabolism; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1111/j.1749-6632.2009.04736.x

The present study was designed to investigate the effects of a novel CaMKII inhibitor SMP-114, which was effective in a collagen-induced arthritis model in rats, on rheumatoid synovial fibroblasts. Rheumatoid synovial fibroblasts (RSF) were cultured under pro-inflammatory (IL-1beta stimulation) and hypoxic conditions. Protein and mRNA expression of HIF-1alpha and the effects of inhibitors of the CaMKII-, PI3K-, and ERK pathway on VEGF and IL-6 production were analyzed. Stimulation under hypoxic conditions induced higher expression of HIF-1alpha and VEGF mRNA than treatment with either IL-1beta or hypoxia alone. However, incubation with a specific CaMKII inhibitor did not result in reduced VEGF production in RSF. CaMKII activation has been reported to be involved in HIF-1alpha stabilization, but incubation with SMP-114, a specific CaMKII inhibitor, had no effect on HIF-1-induced VEGF production by rheumatoid synovial fibroblasts.