Department of Global Innovative Drug, The Graduate School of Chung-Ang University, College of Pharmacy, Chung-Ang University, Seoul 06974, Korea.
BMB Rep. 2022 Nov;55(11):565-570. doi: 10.5483/BMBRep.2022.55.11.098.
Pulmonary arterial hypertension (PAH) is a progressive and devastating disease whose pathogenesis is associated with a phenotypic switch of pulmonary arterial vascular smooth muscle cells (PASMCs). Bone morphogenetic protein (BMP) signaling and potassium two pore domain channel subfamily K member 3 (KCNK3) play crucial roles in PAH pathogenesis. However, the relationship between BMP signaling and KCNK3 expression in the PASMC phenotypic switching process has not been studied. In this study, we explored the effect of BMPs on KCNK3 expression and the role of KCNK3 in the BMP-mediated PASMC phenotypic switch. Expression levels of BMP receptor 2 (BMPR2) and KCNK3 were downregulated in PASMCs of rats with PAH compared to those in normal controls, implying a possible association between BMP/BMPR2 signaling and KCNK3 expression in the pulmonary vasculature. Treatment with BMP2, BMP4, and BMP7 significantly increased KCNK3 expression in primary human PASMCs (HPASMCs). BMPR2 knockdown and treatment with Smad1/5 signaling inhibitor substantially abrogated the BMP-induced increase in KCNK3 expression, suggesting that KCNK3 expression in HPASMCs is regulated by the canonical BMP-BMPR2-Smad1/5 signaling pathway. Furthermore, KCNK3 knockdown and treatment with a KCNK3 channel blocker completely blocked BMP-mediated anti-proliferation and expression of contractile marker genes in HPAMSCs, suggesting that the expression and functional activity of KCNK3 are required for BMP-mediated acquisition of the quiescent PASMC phenotype. Overall, our findings show a crosstalk between BMP signaling and KCNK3 in regulating the PASMC phenotype, wherein BMPs upregulate KCNK3 expression and KCNK3 then mediates BMP-induced phenotypic switching of PASMCs. Our results indicate that the dysfunction and/or downregulation of BMPR2 and KCNK3 observed in PAH work together to induce aberrant changes in the PASMC phenotype, providing insights into the complex molecular pathogenesis of PAH. [BMB Reports 2022; 55(11): 565-570].
肺动脉高压（PAH）是一种进行性和破坏性疾病，其发病机制与肺血管平滑肌细胞（PASMCs）的表型转换有关。骨形态发生蛋白（BMP）信号和钾双孔域通道亚家族 K 成员 3（KCNK3）在 PAH 的发病机制中起着至关重要的作用。然而，BMP 信号与 PASMC 表型转换过程中 KCNK3 表达之间的关系尚未得到研究。在这项研究中，我们探讨了 BMP 对 KCNK3 表达的影响以及 KCNK3 在 BMP 介导的 PASMC 表型转换中的作用。与正常对照相比，PAH 大鼠的 PASMCs 中 BMP 受体 2（BMPR2）和 KCNK3 的表达水平下调，这表明 BMP/BMPR2 信号与肺血管中 KCNK3 的表达之间可能存在关联。BMP2、BMP4 和 BMP7 的处理显著增加了原代人 PASMC（HPASMCs）中 KCNK3 的表达。BMPR2 敲低和 Smad1/5 信号抑制剂的处理显著阻断了 BMP 诱导的 KCNK3 表达增加，表明 HPASMCs 中 KCNK3 的表达受经典 BMP-BMPR2-Smad1/5 信号通路的调节。此外，KCNK3 敲低和 KCNK3 通道阻滞剂的处理完全阻断了 BMP 介导的 HPAMSCs 增殖和收缩标志物基因的表达，表明 KCNK3 的表达和功能活性是 BMP 介导的静止 PASMC 表型获得所必需的。总的来说，我们的研究结果表明 BMP 信号和 KCNK3 在调节 PASMC 表型中存在相互作用，其中 BMPs 上调 KCNK3 的表达，而 KCNK3 则介导 BMP 诱导的 PASMC 表型转换。我们的研究结果表明，PAH 中观察到的 BMPR2 和 KCNK3 的功能障碍和/或下调共同导致 PASMC 表型的异常改变，为 PAH 的复杂分子发病机制提供了新的见解。[BMB 报告 2022；55（11）：565-570]。
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