ASIC1a promotes synovial invasion of rheumatoid arthritis via Ca2+/Rac1 pathway

Niu, Ruowen; Hang, Xiaoyu; Feng, Yongzeng; Zhang, Yihao; Qian, Xuewen; Song, Sujing; Wang, Cong; Tao, Jingjing; Peng, Xiaoqing; Chen, Feihu

doi:10.1016/j.intimp.2019.106089

Cited by 27 publications

(27 citation statements)

References 29 publications

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“…In the past 2 years, our research team has shown that activated ASIC1a induces autophagy, synovial invasion, and synovial inflammation by mediating calcium influx (Gao, Xu, Ge, & Chen, 2019; Niu et al, 2020; Zhang et al, 2020). Calpains are ubiquitous calcium‐activated cysteine proteases.…”

Section: Introductionmentioning

confidence: 99%

Acid‐sensing ion channel 1a mediates acid‐induced pyroptosis through calpain‐2/calcineurin pathway in rat articular chondrocytes

Feng

Zhu

et al. 2020

Cell Biology International

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The pyroptosis is a causative agent of rheumatoid arthritis, a systemic autoimmune disease merged with degenerative articular cartilage. Nevertheless, the precise mechanism of extracellular acidosis on chondrocyte pyroptosis is largely unclear. Acid‐sensing ion channels (ASICs) belong to an extracellular H+‐activated cation channel family. Accumulating evidence has highlighted activation of ASICs induced by extracellular acidosis upregulate calpain and calcineurin expression in arthritis. In the present study, to investigate the expression and the role of acid‐sensing ion channel 1a (ASIC1a), calpain, calcineurin, and NLRP3 inflammasome proteins in regulating acid‐induced articular chondrocyte pyroptosis, primary rat articular chondrocytes were subjected to different pH, different time, and different treatments with or without ASIC1a, calpain‐2, and calcineurin, respectively. Initially, the research results showed that extracellular acidosis‐induced the protein expression of ASIC1a in a pH‐ and time‐dependent manner, and the messenger RNA and protein expressions of calpain, calcineurin, NLRP3, apoptosis‐associated speck‐like protein, and caspase‐1 were significantly increased in a time‐dependent manner. Furthermore, the inhibition of ASIC1a, calpain‐2, or calcineurin, respectively, could decrease the cell death accompanied with the decreased interleukin‐1β level, and the decreased expression of ASIC1a, calpain‐2, calcineurin, and NLRP3 inflammasome proteins. Taken together, these results indicated the activation of ASIC1a induced by extracellular acidosis could trigger pyroptosis of rat articular chondrocytes, the mechanism of which might partly be involved with the activation of calpain‐2/calcineurin pathway.

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Section: Introductionmentioning

confidence: 99%

Acid‐sensing ion channel 1a mediates acid‐induced pyroptosis through calpain‐2/calcineurin pathway in rat articular chondrocytes

Feng

Zhu

et al. 2020

Cell Biology International

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“…In a previous study, we found that ASIC1a, ASIC2a, and ASIC3 were expressed in the articular chondrocytes of rats with AA, and that the expression levels of ASIC1awere significantly higher than those of other subunits (4). More recently, it has been reported that the expression of ASIC1a is significantly increased in human RA synovial tissues, primary human RASF, and the ankle synovium of AA rats (18,19). Table 1 summarizes the tissue and cell distribution of ASIC1a.…”

Section: Tissue and Cell Distribution Of Asic1amentioning

confidence: 99%

“…Our previous studies have demonstrated that ASIC1a is involved in the injury of articular chondrocytes that is caused by increased intracellular calcium ([Ca 2+ ]i) induced by extracellular acidification; this can be significantly attenuated by the use of amiloride and the ASIC1a-specific blocker psalmotoxin 1 (PCTX-1) (15)(16)(17). Recently, it has been indicated that ASIC1a is highly expressed in RA synovial tissues and RA synovial fibroblasts (RASF); it also induces synovial inflammation and invasion, which are downregulated by ASIC1a-RNAi and PCTX-1 while they are increased by the overexpression of ASIC1a (18,19). Thus, ASIC1a may be a potential therapeutic target for RA.…”

Section: Introductionmentioning

confidence: 99%

Acid-Sensing Ion Channel-1a in Articular Chondrocytes and Synovial Fibroblasts: A Novel Therapeutic Target for Rheumatoid Arthritis

Chen

2021

Front. Immunol.

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Acid-sensing ion channel 1a (ASIC1a) is a member of the extracellular H+-activated cation channel family. Emerging evidence has suggested that ASIC1a plays a crucial role in the pathogenesis of rheumatoid arthritis (RA). Specifically, ASIC1a could promote inflammation, synovial hyperplasia, articular cartilage, and bone destruction; these lead to the progression of RA, a chronic autoimmune disease characterized by chronic synovial inflammation and extra-articular lesions. In this review, we provided a brief overview of the molecular properties of ASIC1a, including the basic biological characteristics, tissue and cell distribution, channel blocker, and factors influencing the expression and function, and focused on the potential therapeutic targets of ASIC1a in RA and possible mechanisms of blocking ASIC1a to improve RA symptoms, such as regulation of apoptosis, autophagy, pyroptosis, and necroptosis of articular cartilage, and synovial inflammation and invasion of fibroblast-like cells in synovial tissue.

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“…Acidsensing ion channels(ASICs) are cation channels activated by extracellular acidi cation and play an important role in the pathological process of many diseases such as cerebral ischemia,rheumatoid arthritis and systemic sclerosis. ASIC1a is one member among 6 subunits of ASICs, which is responsible for Ca2+ transportation and is involved in in ammation, tumor, and ischemic injury in central nervous system and non-neuronal tissues [3]. Our previous research found the expression of ASIC1a in vascular endothellial cells could be stimulated by serum IgA1 from HSP patients under acidic environment [4], and acid-inhibiting agents omeprazole can signi cantly improve the clinical manifestations of HSP patients [5].…”

Section: Introductionmentioning

confidence: 99%

Involvement of Acid-Sensing Ion Channel 1a Contribute to The Effect of Extracellular Acidosis on Vascular Endothelialcell Damage of Henoch-Schönlein Purpura Patients

Wang

Yan

Zhou

et al. 2021

Preprint

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Introduction: Henoch-Schönlein purpura (HSP) is a common kind of systematic vasculitis in children characterized by rash, joint pain,abdominal symptoms and renal disease,the detail pathogenesis of HSP has not been elucidated.Acid-sensing ion channels (ASICs) is a proton-gated sodium selective channel that belongs to Degenerin /epithelial Sodium Channel(DEG/ENaC) superfamily,previous research found the expression of ASIC1a in vascular endothellial cells could be stimulated by serum IgA1 from HSP patients under acidic environment.This study aims to investigate the molecular mechanisms of silencing of acid-sensing ion channel 1a(ASIC1a) protects the vascular endothelial cells from Henoch-Schonlein purpura(HSP) patients.Methods:Human dermal microvascular endothelial cells ( HDMVEC) were cultured in vitro，siRNA sequences were designed for the coding region of human ASIC1a gene and HDMVEC cells were transfected with recombinant lentivirus( LV) -sh-ASIC1a． The control group ( NC group) without virus transfection and LV-sh-ASIC1a transfection group ( si-ASIC1a group) were set up． The expression of transfixed ASIC1a gene was detected by RT-PCR． After virus transfection 72 h，serum IgA1from HSP patients and serum IgA1 of normal children were added into HDMVEC cells． ASIC1a and cytoskeleton protein ( sm-α f-actin，MLCK) mRNA and protein expressions were detected by real-time PCR and Western blotting Methods.The binding activity of NF- κB with DNA in HDMVEC was determined by electrophoretic mobility shift assay (EMSA).The whole-cell patch-clamp technique was used to record the current changes and electrophysiological characteristics of ASICs and calcium in HDMVEC.Results：Cytoskeleton protein ( sm-α f-actin，MLCK) mRNA and protein expressions in the group of si-ASIC1a group were significantly increased compared with the NC control group( P ＜ 0． 01) ．The HSP serum and silencing of ASIC1a had no significant effect on the binding activity of NF-κB with DNA in HDMVEC. Compared with the NC control group, the ASICS current and calcium overload of the si-ASIC1A group were reduced( P ＜ 0． 01) ．Conclusion: Silencing ASIC1a can protect HSP vascular endothelial cell injury by inhibiting ASIC1-related calcium influx and reducing the overload of calcium ,not the NF- κB signaling pathway.

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ASIC1a promotes synovial invasion of rheumatoid arthritis via Ca2+/Rac1 pathway

Cited by 27 publications

References 29 publications

Acid‐sensing ion channel 1a mediates acid‐induced pyroptosis through calpain‐2/calcineurin pathway in rat articular chondrocytes

Acid‐sensing ion channel 1a mediates acid‐induced pyroptosis through calpain‐2/calcineurin pathway in rat articular chondrocytes

Acid-Sensing Ion Channel-1a in Articular Chondrocytes and Synovial Fibroblasts: A Novel Therapeutic Target for Rheumatoid Arthritis

Involvement of Acid-Sensing Ion Channel 1a Contribute to The Effect of Extracellular Acidosis on Vascular Endothelialcell Damage of Henoch-Schönlein Purpura Patients

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ASIC1a promotes synovial invasion of rheumatoid arthritis via Ca2+/Rac1 pathway

Cited by 27 publications

References 29 publications

Acid‐sensing ion channel 1a mediates acid‐induced pyroptosis through calpain‐2/calcineurin pathway in rat articular chondrocytes

Acid‐sensing ion channel 1a mediates acid‐induced pyroptosis through calpain‐2/calcineurin pathway in rat articular chondrocytes

Acid-Sensing Ion Channel-1a in Articular Chondrocytes and Synovial Fibroblasts: A Novel Therapeutic Target for Rheumatoid Arthritis

Involvement of Acid-Sensing Ion Channel 1a&nbsp;Contribute to&nbsp;The Effect of Extracellular Acidosis on&nbsp;Vascular Endothelialcell Damage&nbsp;of&nbsp;Henoch-Schönlein&nbsp;Purpura&nbsp;Patients

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Involvement of Acid-Sensing Ion Channel 1a Contribute to The Effect of Extracellular Acidosis on Vascular Endothelialcell Damage of Henoch-Schönlein Purpura Patients