Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance and obliterative pulmonary vascular remodelling (PVR). The imbalance between the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMCs) is an important cause of PVR leading to PAH. Mitochondria play a key role in the production of hypoxia‐induced pulmonary hypertension (HPH). However, there are still many issues worth studying in depth. In this study, we demonstrated that NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 like 2 (NDUFA4L2) was a proliferation factor and increased in vivo and in vitro through various molecular biology experiments. HIF‐1α was an upstream target of NDUFA4L2. The plasma levels of 4‐hydroxynonene (4‐HNE) were increased both in PAH patients and hypoxic PAH model rats. Knockdown of NDUFA4L2 decreased the levels of malondialdehyde (MDA) and 4‐HNE in human PASMCs in hypoxia. Elevated MDA and 4‐HNE levels might be associated with excessive ROS generation and increased expression of 5‐lipoxygenase (5‐LO) in hypoxia, but this effect was blocked by siNDUFA4L2. Further research found that p38‐5‐LO was a downstream signalling pathway of PASMCs proliferation induced by NDUFA4L2. Up‐regulated NDUFA4L2 plays a critical role in the development of HPH, which mediates ROS production and proliferation of PASMCs, suggesting NDUFA4L2 as a potential new therapeutic target for PAH.

中文翻译：

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平滑肌中的 NDUFA4L2 促进缺氧性肺动脉高压的血管重塑

肺动脉高压 (PAH) 的特征是肺血管阻力逐渐增加和闭塞性肺血管重塑 (PVR)。肺动脉平滑肌细胞(PASMCs)增殖与凋亡失衡是PVR导致PAH的重要原因。线粒体在缺氧性肺动脉高压（HPH）的产生中起关键作用。但是，仍有许多问题值得深入研究。在这项研究中，我们通过各种分子生物学实验证明了 NADH 脱氢酶（泛醌）1 α 亚复合物 4 样 2 (NDUFA4L2) 是一种增殖因子，并且在体内和体外都会增加。HIF-1α 是 NDUFA4L2 的上游靶点。PAH 患者和低氧 PAH 模型大鼠的血浆 4-羟基壬烯 (4-HNE) 水平均升高。NDUFA4L2 的敲低降低了缺氧时人 PASMCs 中丙二醛 (MDA) 和 4-HNE 的水平。升高的 MDA 和 4-HNE 水平可能与过量 ROS 的产生和缺氧时 5-脂氧合酶 (5-LO) 的表达增加有关，但这种作用被 siNDUFA4L2 阻断。进一步研究发现 p38-5-LO 是 NDUFA4L2 诱导的 PASMCs 增殖的下游信号通路。上调的 NDUFA4L2 在 HPH 的发展中起关键作用，它介导 ROS 的产生和 PASMCs 的增殖，表明 NDUFA4L2 是 PAH 潜在的新治疗靶点。但这种作用被 siNDUFA4L2 阻断。进一步研究发现 p38-5-LO 是 NDUFA4L2 诱导的 PASMCs 增殖的下游信号通路。上调的 NDUFA4L2 在 HPH 的发展中起关键作用，它介导 ROS 的产生和 PASMCs 的增殖，表明 NDUFA4L2 是 PAH 潜在的新治疗靶点。但这种作用被 siNDUFA4L2 阻断。进一步研究发现 p38-5-LO 是 NDUFA4L2 诱导的 PASMCs 增殖的下游信号通路。上调的 NDUFA4L2 在 HPH 的发展中起关键作用，它介导 ROS 的产生和 PASMCs 的增殖，表明 NDUFA4L2 是 PAH 潜在的新治疗靶点。