Role for CaMKII Inhibition in Rheumatoid Arthritis Effects on HIF-1-Induced VEGF Production by Rheumatoid Synovial Fibroblasts

Background and aims: 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. Methods: Rheumatoid synovial fibroblasts (RSF) were cultured under pro-inflammatory (IL-1 beta stimulation) and hypoxic conditions. Protein and mRNA expression of HIF-1 alpha and the effects of inhibitors of the CaMKII-, PI3K-, and ERK pathway on VEGF and IL-6 production were analyzed. Results: Stimulation under hypoxic conditions induced higher expression of HIF-1 alpha and VEGF mRNA than treatment with either IL-1 beta or hypoxia alone. However, incubation with a specific CaMKII inhibitor did not result in reduced VEGF production in RSF. Conclusions: CaMKII activation has been reported to be involved in HIF-1 alpha stabilization, but incubation with SMP-114, a specific CaMKII inhibitor, had no effect on HIF-1-induced VEGF production by rheumatoid synovial fibroblasts.