SKF96365 activates calcium-sensing receptors in pulmonary arterial smooth muscle cells
SKF96365 activates calcium-sensing receptors in pulmonary arterial smooth muscle cells
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SKF96365 激活肺动脉平滑肌细胞中的钙敏感受体
DOI：
10.1016/j.bbrc.2022.03.121
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发表时间：
2022
影响因子：
3.1
通讯作者：
Yamamura Hisao
中科院分区：
文献类型：
--
作者：
Miyaki Riko;Yamamura Aya;Kawade Akiko;Fujiwara Moe;Kondo Rubii;Suzuki Yoshiaki;Yamamura Hisao
在肺动脉平滑肌细胞(PASMCs)中，细胞内钙离子浓度([Ca~(2+)]Cyt)的升高参与了细胞收缩和增殖等多种生理过程。然而，慢性[Ca~(2+)]细胞升高会引起肺血管收缩和血管重塑，导致肺动脉高压(PAH)。因此，[Ca~(2+)]细胞信号在PASMCs的生理和病理功能调节中起着重要作用。本研究观察了SKF96365对正常人和特发性肺动脉高压(IPAH)患者PASMCs[Ca~(2+)]细胞的影响。SKF96365被广泛用作非选择性阳离子通道的阻滞剂。SKF96365对正常PASMCs的静息[Ca~(2+)]-Cytin无影响。然而，SKF96365以浓度依赖的方式增加[Ca~(2+)]Cytin Ipah-PASMC(EC_(50)=1.18μM)。IPAH-PASMCs的钙敏感受体(CaSR)表达高于正常PASMCs。CaSR拮抗剂NPS2143和Calhex 231可抑制SKF96365诱导的细胞内钙离子浓度升高。SKF96365可促进CaSR介导的细胞内钙离子浓度升高，而NPS2143或Calhex 231则可阻断该作用。此外，通过抑制CaSRs的siRNA表达，SKF96365诱导的细胞内钙离子浓度升高也被抑制。综上所述，SKF96365激活IPAH-PASMCs中的CaSR，并促进[Ca~(2+)]细胞信号传导。
In pulmonary arterial smooth muscle cells (PASMCs), an increase in the cytosolic Ca2+concentration ([Ca2+]cyt) is involved in many physiological processes such as cell contraction and proliferation. However, chronic [Ca2+]cytincreases cause pulmonary vasoconstriction and vascular remodeling, resulting in pulmonary arterial hypertension (PAH). Therefore, [Ca2+]cytsignaling plays a substantial role in the regulation of physiological and pathological functions in PASMCs. In the present study, the effects of SKF96365 on [Ca2+]cytwere examined in PASMCs from normal subjects and idiopathic pulmonary arterial hypertension (IPAH) patients. SKF96365 is widely used as a blocker of non-selective cation channels. SKF96365 did not affect the resting [Ca2+]cytin normal-PASMCs. However, SKF96365 increased [Ca2+]cytin IPAH-PASMCs in a concentration-dependent manner (EC50= 18 μM). The expression of Ca2+-sensing receptors (CaSRs) was higher in IPAH-PASMCs than in normal-PASMCs. The SKF96365-induced [Ca2+]cytincrease was inhibited by CaSR antagonists, NPS2143 and Calhex 231. The CaSR-mediated [Ca2+]cytincrease was facilitated by SKF96365 and the activation was blocked by NPS2143 or Calhex 231. In addition, the SKF96365-induced [Ca2+]cytincrease was reduced by siRNA knockdown of CaSRs. Taken together, SKF96365 activates CaSRs in IPAH-PASMCs and promotes [Ca2+]cytsignaling.