Department of Geriatric Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China.
Department of Respiratory Medicine, The First Affiliated Hospital, Wenzhou Medical University, Shangcai Village, South Baixiang town, Ouhai District, Wenzhou 325000, Zhejiang, PR China.
Exp Cell Res. 2018 Jan 15;362(2):311-323. doi: 10.1016/j.yexcr.2017.11.032. Epub 2017 Nov 28.
Pulmonary arterial hypertension (PAH) is a devastating disease characterized by high pulmonary artery pressure. It is reported that microRNA-204 (miR-204) plays an important role in the development of PAH. Calcitriol [1,25-dihydroxyvitamin D3, 1,25(OH)D] mediates multiple pathophysiological processes. The aim of the current study was to explore the role of 1,25(OH)D in PAH. PAH was induced in rats and rat pulmonary arterial endothelial cells (PAECs) were isolated as in vitro PAH model. The mean pulmonary artery pressure, morphologic changes, and expressions of transforming growth factor-beta1 (Tgfbr2), Smad2/7, alpha smooth muscle actin (α-SMA), and p21 were then measured. Furthermore, the effect of 1,25(OH)D on rat PAECs with or without hypoxia treatment was also assessed by measuring the proliferation, migration, and cell cycle distribution of PAECs. The potential targets of miR-204 were also predicted and validated with a dual-luciferase reporter system. Then the role of miR-204 and Tgfbr2 in the anti-PAH effect of 1,25(OH)D was further explored by modulating the expression of the two genes. The overall pulmonary hypertension and hypoxia-induced proliferation and migration of PAECs were attenuated by administration of 1,25(OH)D, which was associated with the suppressed expressions of Tgfbr2, α-SMA, and Smad7 and induced expressions of miR-204, p21 and Smad2 both in vitro and in vivo. Moreover, the luciferase reporter assay identified Tgfbr2 as a novel direct target of miR-204. Both overexpression of miR-204 and inhibition of Tgfbr2 would strengthen the effect of 1,25(OH)D administration. Findings outlined in the current study demonstrated that 1,25(OH)D was a promising therapeutic modality for treatment of PAH, function of which was exerted through miR-204 mediated Tgfbr2 signaling.
肺动脉高压（PAH）是一种以肺动脉高压为特征的破坏性疾病。据报道，微小 RNA-204（miR-204）在 PAH 的发展中起重要作用。钙三醇[1,25-二羟基维生素 D3，1,25（OH）D]介导多种病理生理过程。本研究旨在探讨 1,25（OH）D 在 PAH 中的作用。在大鼠中诱导 PAH，并分离大鼠肺动脉内皮细胞（PAECs）作为体外 PAH 模型。然后测量平均肺动脉压、形态变化以及转化生长因子-β1（Tgfbr2）、Smad2/7、α平滑肌肌动蛋白（α-SMA）和 p21 的表达。此外，还通过测量缺氧处理前后 1,25（OH）D 对大鼠 PAECs 的增殖、迁移和细胞周期分布的影响来评估 1,25（OH）D 的作用。还通过双荧光素酶报告系统预测和验证了 miR-204 的潜在靶标。然后通过调节两个基因的表达进一步探讨了 miR-204 和 Tgfbr2 在 1,25（OH）D 抗 PAH 作用中的作用。1,25（OH）D 的给药减轻了整体肺动脉高压和缺氧诱导的 PAECs 增殖和迁移，这与体外和体内 Tgfbr2、α-SMA 和 Smad7 的表达受抑以及 miR-204、p21 和 Smad2 的表达上调有关。此外，荧光素酶报告实验鉴定 Tgfbr2 为 miR-204 的一个新的直接靶标。miR-204 的过表达和 Tgfbr2 的抑制均可增强 1,25（OH）D 给药的作用。本研究的结果表明，1,25（OH）D 是治疗 PAH 的一种有前途的治疗方法，其功能是通过 miR-204 介导的 Tgfbr2 信号发挥作用。
