CRACチャネル阻害薬は肝星細胞の活性化を抑制する

抄録

Hepatic stellate cells are liver-specific pericytes that play a critical role in the development of hepatic fibrosis. During liver injury, these cells transdifferentiate from the quiescent phenotype into the activated phenotype, resulting in enhanced cell proliferation and extracellular matrix production. The Ca²⁺ release-activated Ca²⁺ (CRAC) channels are expressed in many types of tissues and involved in the regulation of physiological and pathological processes. However, the involvement of CRAC channels on hepatic fibrosis remains unclear. In the present study, we investigated the pathophysiological roles of CRAC channels in human hepatic stellate LX-2 cells. Expression analysis revealed that LX-2 cells expressed Orai1 and STIM1 mRNAs which are the major components of CRAC channels. TGF-β1 caused the upregulation of myofibroblast markers, α-SMA and Col1α1, in LX-2 cells. The upregulation was markedly reduced by a non-specific CRAC channel blocker, BTP-2. BTP-2 clearly inhibited store-operated Ca²⁺ entry in LX-2 cells. In addition, BTP-2 significantly attenuated the proliferation of LX-2 cells. These results strongly suggest that CRAC channels are functionally expressed in hepatic stellate cells and contribute to extracellular matrix production and cell proliferation.