Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, 28040 Madrid, Spain.
Ciber Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain.
Int J Mol Sci. 2023 Aug 2;24(15):12350. doi: 10.3390/ijms241512350.
Recent evidence suggests that vitamin D is involved in the development of pulmonary arterial hypertension (PAH). The aim of this study was to analyze the electrophysiological and contractile properties of pulmonary arteries (PAs) in vitamin D receptor knockout mice (). PAs were dissected and mounted in a wire myograph. Potassium membrane currents were recorded in freshly isolated PA smooth muscle cells (PASMCs) using the conventional whole-cell configuration of the patch-clamp technique. Potential vitamin D response elements (VDREs) in Kv7 channels coding genes were studied, and their protein expression was analyzed. mice did not show a pulmonary hypertensive phenotype, as neither right ventricular hypertrophy nor endothelial dysfunction was apparent. However, resistance PA from these mice exhibited increased response to retigabine, a Kv7 activator, compared to controls and heterozygous mice. Furthermore, the current sensitive to XE991, a Kv7 inhibitor, was also higher in PASMCs from knockout mice. A possible VDRE was found in the gene coding for KCNE4, the regulatory subunit of Kv7.4. Accordingly, mice showed an increased expression of KCNE4 in the lungs, with no changes in Kv7.1 and Kv7.4. These results indicate that the absence of in mice, as occurred with vitamin D deficient rats, is not sufficient to induce PAH. However, the contribution of Kv7 channel currents to the regulation of PA tone is increased in Vdr mice, resembling animals and humans suffering from PAH.
最近的证据表明，维生素 D 参与肺动脉高压（PAH）的发展。本研究旨在分析维生素 D 受体敲除小鼠（）肺动脉的电生理和收缩特性。将肺动脉分离并安装在金属丝肌动描记器中。使用膜片钳技术的常规全细胞构型记录新鲜分离的肺动脉平滑肌细胞（PASMC）中的钾膜电流。研究 Kv7 通道编码基因中的潜在维生素 D 反应元件（VDRE），并分析其蛋白表达。Vdr 敲除小鼠没有表现出肺动脉高压表型，因为右心室肥厚和内皮功能障碍并不明显。然而，与对照组和杂合子小鼠相比，这些小鼠的阻力型 PA 对 Kv7 激活剂 retigabine 的反应增加。此外，对 Kv7 抑制剂 XE991 敏感的电流在敲除小鼠的 PASMC 中也更高。在编码 Kv7.4 的调节亚基 KCNE4 的基因中发现了一个可能的 VDRE。相应地，Vdr 敲除小鼠的肺部 KCNE4 表达增加，而 Kv7.1 和 Kv7.4 没有变化。这些结果表明，与维生素 D 缺乏的大鼠一样，Vdr 敲除小鼠体内维生素 D 的缺乏不足以诱导 PAH。然而，在 Vdr 小鼠中，Kv7 通道电流对 PA 张力的调节作用增加，类似于患有 PAH 的动物和人类。
