Abstract
BackgroundResveratrol was reported to trigger the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats but the subcellular mechanism remains unclear. Since ER stress, mitochondrial dysfunction and oxidative stress were involved in the effects of resveratrol with imbalance of calcium bio-transmission, store operated calcium entry (SOCE), a novel intracellular calcium regulatory pathway, may also participate in this process.ResultsIn the present study, Resveratrol was found to suppress ORAI1 expression of a dose dependent manner while have no evident effects on STIM1 expressive level. Besides, resveratrol had no effects on ATP or TG induced calcium depletion but present partly dose-dependent suppression of SOCE. On the one hand, microinjection of ORAI1 overexpressed vector in sick toe partly counteracted the therapeutic effects of resveratrol on adjuvant arthritis and serum inflammatory cytokine including IL-1, IL-6, IL-8, IL-10 and TNF-α. On the other hand, ORAI1 SiRNA injection provided slight relief to adjuvant arthritis in rats. In addition, ORAI1 overexpression partly diminished the alleviation of hemogram abnormality induced by adjuvant arthritis after resveratrol treatment while ORAI1 knockdown presented mild resveratrol-like effect on hemogram in rats model.ConclusionThese results indicated that resveratrol reduced store-operated Ca2+ entry and enhanced the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats model via targeting ORAI1–STIM1 complex, providing a theoretical basis for ORAI1 targeted therapy in future treatment with resveratrol on rheumatoid arthritis.
Highlights
Resveratrol was reported to trigger the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats but the subcellular mechanism remains unclear
During the process of store operated calcium entry (SOCE), the emptying of calcium stores can be sensed by stromal interaction molecule 1 (STIM1), and STIM1 is transferred to the cell membrane to bind and activate calcium release-activated calcium channel protein 1 (ORAI1) to form a multimeric channel, which mediates the influx of extracellular calcium to supplements the loss of the calcium reservoir [10]
Resveratrol reduces adenosine triphosphate (ATP) or TG induced SOCE in fibroblast like synoviacytes (FLSs) FLSs were treated with diverse dose of resveratrol with or without 5 μM H 2O2 for 48 h
Summary
Resveratrol was reported to trigger the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats but the subcellular mechanism remains unclear. Since ER stress, mitochondrial dysfunction and oxidative stress were involved in the effects of resveratrol with imbalance of calcium bio-transmission, store operated calcium entry (SOCE), a novel intracellular calcium regulatory pathway, may participate in this process. Recent studies have shown that SOCs play an important role in the apoptosis process of various types of cells such as neuronal cells and hepatocarcinoma cells, and these effects are closely related to the regulation of STIM1, ORAI1 and their subtypes [14, 15]. Based on the previous research, our group further explored the specific mechanism of resveratrol-induced apoptosis in fibroblasts within 5 μM H 2O2, and attempted to elucidate the regulation of resveratrol on SOCE and two essential SOCs, STIM1 and ORAI1. If there is some influence, whether the reverse adjustment of the effect can reverse the original effect need to be explored
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