Miyaki Riko, Yamamura Aya, Kawade Akiko, Fujiwara Moe, Kondo Rubii, Suzuki Yoshiaki, Yamamura Hisao
Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabedori Mizuhoku, Nagoya, 467-8603, Japan.
Department of Physiology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.
Biochem Biophys Res Commun. 2022 Jun 4;607:44-48. doi: 10.1016/j.bbrc.2022.03.121. Epub 2022 Mar 25.
In pulmonary arterial smooth muscle cells (PASMCs), an increase in the cytosolic Ca concentration ([Ca]) is involved in many physiological processes such as cell contraction and proliferation. However, chronic [Ca] increases cause pulmonary vasoconstriction and vascular remodeling, resulting in pulmonary arterial hypertension (PAH). Therefore, [Ca] signaling plays a substantial role in the regulation of physiological and pathological functions in PASMCs. In the present study, the effects of SKF96365 on [Ca] were 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 [Ca] in normal-PASMCs. However, SKF96365 increased [Ca] in IPAH-PASMCs in a concentration-dependent manner (EC = 18 μM). The expression of Ca-sensing receptors (CaSRs) was higher in IPAH-PASMCs than in normal-PASMCs. The SKF96365-induced [Ca] increase was inhibited by CaSR antagonists, NPS2143 and Calhex 231. The CaSR-mediated [Ca] increase was facilitated by SKF96365 and the activation was blocked by NPS2143 or Calhex 231. In addition, the SKF96365-induced [Ca] increase was reduced by siRNA knockdown of CaSRs. Taken together, SKF96365 activates CaSRs in IPAH-PASMCs and promotes [Ca] signaling.
在肺动脉平滑肌细胞（PASMCs）中，胞质钙浓度（[Ca]）的升高参与许多生理过程，如细胞收缩和增殖。然而，慢性[Ca]升高会导致肺血管收缩和血管重塑，进而引发肺动脉高压（PAH）。因此，[Ca]信号在PASMCs生理和病理功能的调节中起着重要作用。在本研究中，检测了SKF96365对正常受试者和特发性肺动脉高压（IPAH）患者PASMCs中[Ca]的影响。SKF96365被广泛用作非选择性阳离子通道阻滞剂。SKF96365不影响正常PASMCs中的静息[Ca]。然而，SKF96365以浓度依赖性方式增加IPAH-PASMCs中的[Ca]（EC = 18 μM）。IPAH-PASMCs中钙敏感受体（CaSRs）的表达高于正常PASMCs。SKF96365诱导的[Ca]升高被CaSR拮抗剂NPS2143和Calhex 231抑制。SKF96365促进CaSR介导的[Ca]升高，且该激活被NPS2143或Calhex 231阻断。此外，CaSRs的siRNA敲低降低了SKF96365诱导的[Ca]升高。综上所述，SKF96365激活IPAH-PASMCs中的CaSRs并促进[Ca]信号传导。
