Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA.
Acta Physiol (Oxf). 2024 Sep;240(9):e14212. doi: 10.1111/apha.14212. Epub 2024 Jul 29.
Chronic hypoxia is a common cause of pulmonary hypertension (PH). We test the hypothesis that microRNA-210 (miR-210) mediates hypoxia-induced PH by targeting mitochondrial metabolism and increasing reactive oxygen species (mtROS) production in the lungs.
Adult wildtype (WT) or miR-210 knockout (KO) mice were exposed to hypoxia (10.5% O) or normoxia for 4 weeks. We measured miR-210 levels, right ventricular systolic pressure (RVSP), and histological changes in heart and lung tissues. Mitochondrial bioenergetics and mtROS production were assessed in isolated lung mitochondria.
Hypoxia increased right ventricular wall thickness and pulmonary vessel wall muscularization in WT, but not miR-210 KO mice. No sex differences were observed. In male mice, hypoxia increased miR-210 levels in the lung and RVSP, which were abrogated by miR-210 deficiency. Hypoxia upregulated mitochondrial oxygen consumption rate and mtROS flux, which were negated in miR-210 KO animals. In addition, chronic hypoxia increased macrophage accumulation in lungs of WT, but not miR-210 KO mice. Moreover, miR-210 overexpression in lungs of WT animals recapitulated the effects of hypoxia and increased mitochondrial oxygen consumption rate, mtROS flux, right ventricular wall thickness, pulmonary vessel wall muscularization and RVSP. MitoQ revoked the effects of miR-210 on lung mitochondrial bioenergetics, right ventricular and pulmonary vessel remodeling and RVSP.
Our findings with loss-of-function and gain-of-function approaches provide explicit evidence that miR-210 mediates hypoxia-induced PH by upregulating mitochondrial bioenergetics and mtROS production in a murine model, revealing new insights into the mechanisms and therapeutic targets for treatment of PH.
慢性缺氧是肺动脉高压（PH）的常见原因。我们通过测试假设来验证，miR-210 通过靶向线粒体代谢并增加肺部的活性氧（mtROS）产生来介导缺氧诱导的 PH。
成年野生型（WT）或 miR-210 敲除（KO）小鼠暴露于低氧（10.5% O）或常氧 4 周。我们测量了 miR-210 水平、右心室收缩压（RVSP）以及心和肺组织的组织学变化。在分离的肺线粒体中评估线粒体生物能学和 mtROS 产生。
低氧增加了 WT 但不是 miR-210 KO 小鼠的右心室壁厚度和肺血管壁肌化。未观察到性别差异。在雄性小鼠中，低氧增加了肺和 RVSP 中的 miR-210 水平，而 miR-210 缺失则消除了这种增加。低氧上调了线粒体耗氧率和 mtROS 通量，而在 miR-210 KO 动物中则被否定。此外，慢性低氧增加了 WT 但不是 miR-210 KO 小鼠肺部的巨噬细胞积累。此外，WT 动物肺部的 miR-210 过表达再现了低氧的作用，增加了线粒体耗氧率、mtROS 通量、右心室壁厚度、肺血管壁肌化和 RVSP。MitoQ 逆转了 miR-210 对肺线粒体生物能学、右心室和肺血管重塑以及 RVSP 的影响。
我们通过功能丧失和功能获得的方法得出的发现，提供了明确的证据表明 miR-210 通过上调线粒体生物能学和 mtROS 产生来介导缺氧诱导的 PH，这为 PH 治疗的机制和治疗靶点提供了新的见解。
