ASIC2a overexpression enhances the protective effect of PcTx1 and APETx2 against acidosis-induced articular chondrocyte apoptosis and cytotoxicity.

Acid hydrarthrosis is another important pathological character in rheumatoid arthritis (RA), and acid-sensing ion channel 1a (ASIC1a) plays a destructive role in acidosis-induced articular chondrocyte cytotoxicity. Recently, ASIC2a has been reported to possess neuroprotective effect on acidosis-induced injury of neuronal cells. However, whether ASIC2a has an enhanced effect on the protective effect of blocking ASIC1a and ASIC3 against acid-induced chondrocyte apoptosis is still unclear. The aim of present study was to investigate the chondroprotective effect of ASIC2a with PcTx1 (ASIC1a specific blocker) and APETx2 (ASIC3 specific blocker) on acidosis-induced chondrocyte apoptosis. Our results revealed that acid (pH 6.0) decreased the cell viability and induced apoptosis of articular chondrocytes. PcTx1 and APETx2 combination significantly attenuated acidosis-induced chondrocyte cytotoxicity due to inhibit apoptosis, and this role could be enhanced by ASIC2a overexpression compared with the PcTx1 and APETx2 combination alone group. Moreover, both the [Ca2+]i levels and the levels of phosphorylated ERK1/2 as well as p38 were further reduced in acidosis-induced chondrocytes after ASIC2a overexpression in the presence of PcTx1 and APETx2. Furthermore, ASIC2a overexpression also reduced acid-induced the expression of ASIC1a. In addition, ASIC2a overexpression further promoted the PcTx1 and APETx2-increased levels of type II collagen in acidosis-induced chondrocytes. Taken together, the current data suggested that ASIC2a overexpression might enhance the anti-apoptotic and protective role of PcTx1 and APETx2 against acid-induced rat articular chondrocyte apoptosis by regulating ASIC1a expression and the [Ca2+]i levels and at least in part, suppressing p38 and ERK1/2 MAPK signaling pathways.

Inhibition of acid-sensing ion channel 1a in hepatic stellate cells attenuates PDGF-induced activation of HSCs through MAPK pathway.

Acid-sensing ion channels (ASICs), a group of Na(+)-selective and Ca(2+)-permeant ligand-gated cation channels, can be transiently activated by extracellular acid. Among seven subunits of ASICs, acid-sensing ion channel 1a (ASIC1a), which is responsible for Ca(2+) transportation, is elevated in response to inflammation, tumor, and ischemic injury in central nervous system and non-neuronal tissues. In this study, we demonstrated for the first time the presence of ASIC1a in rat liver and hepatic stellate cells (HSCs). Furthermore, the expression of ASIC1a was increased in primary HSCs and liver tissues of CCl4-treated rats, suggesting that ASIC1a may play certain role in liver fibrosis. Interestingly, we identified that the level of ASIC1a was significantly elevated in response to platelet-derived growth factor (PDGF) induction in a time- and dose-dependent manner. It was also established that Ca(2+)-transporting ASIC1a was involved in acid-induced injury of different cell types. Moreover, inhibition or silencing of ASIC1a was able to inhibit PDGF-induced pro-fibrogenic effects of activated rat HSCs, including cell activation, de novo synthesis of extracellular matrix components through mitogen-activated protein kinase signaling pathway. Collectively, our studies identified that ASIC1a was expressed in rat liver and HSCs and provided a strong evidence for the involvement of the ASIC1a in the progression of hepatic fibrosis.