TRPV1 mediates cell death in rat synovial fibroblasts through calcium entry-dependent ROS production and mitochondrial depolarization.
Synoviocyte hyperplasia is critical for rheumatoid arthritis, therefore, potentially an important target for therapeutics. It was found in this work that a TRPV1 agonist capsaicin, and acidic solution (pH 5.5) induced increases in cytosolic calcium concentration ([Ca(2+)](c)) and reactive oxygen species (ROS) production in synoviocytes isolated from a rat model of collagen-induced arthritis. The increases in both [Ca(2+)](c) and ROS production were completely abolished in calcium-free buffer or by a TRPV1 antagonist capsazepine. Further experiments revealed that capsaicin and pH 5.5 solution caused mitochondrial membrane depolarization and reduction in cell viability; such effects were inhibited by capsazepine, or the NAD(P)H oxidase inhibitor diphenylene iodonium. Both capsaicin and pH 5.5 buffer induced apoptosis as shown by nuclear condensation and fragmentation. Furthermore, RT-PCR readily detected TRPV1 mRNA expression in the isolated synoviocytes. Taken together, these data indicated that TRPV1 activation triggered synoviocyte death by [Ca(2+)](c) elevation, ROS production, and mitochondrial membrane depolarization.
Hu
Fen
F
Department of Biophysics, The School of Physics, The Ministry of Education Key Laboratory of Bioactive Materials, Nankai University, #94 Weijin Road, Nankai District, Tianjin 300071, China.
Sun
Wen Wu
WW
Zhao
Xiao Ting
XT
Cui
Zong Jie
ZJ
Yang
Wen Xiu
WX
D000818:Animals; D017209:Apoptosis; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D008297:Male; D053078:Membrane Potential, Mitochondrial; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009861:Onium Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050916:TRPV Cation Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
D009861:Onium Compounds; D017382:Reactive Oxygen Species; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C007517:diphenyleneiodonium; D019255:NADPH Oxidases; C071423:capsazepine; D002211:Capsaicin; D002118:Calcium