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


RESULTS
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.


CONCLUSIONS
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.
Westra
Johanna
J
Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, The Netherlands. j.westra@med.umcg.nl
Brouwer
Elisabeth
E
Bouwman
Erwin
E
Doornbos-van der Meer
Berber
B
Posthumus
Marcel D
MD
van Leeuwen
Miek A
MA
Limburg
Pieter C
PC
Ueda
Yutaka
Y
Kallenberg
Cees G M
CG
D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001596:Benzylamines / Q000494:pharmacology; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D000096926:Benzenesulfonamides
D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002867:Chromones; D005419:Flavonoids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D015850:Interleukin-6; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C497442:HIF1A protein, human; C072105:KN 93; D000096926:Benzenesulfonamides; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one