Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, California.
Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado.
Am J Physiol Lung Cell Mol Physiol. 2022 Sep 1;323(3):L355-L371. doi: 10.1152/ajplung.00039.2022. Epub 2022 Jun 28.
Dysregulated metabolism characterizes both animal and human forms of pulmonary hypertension (PH). Enzymes involved in fatty acid metabolism have previously not been assessed in human pulmonary arteries affected by pulmonary arterial hypertension (PAH), and how inhibition of fatty acid oxidation (FAO) may attenuate PH remains unclear. Fatty acid metabolism gene transcription was quantified in laser-dissected pulmonary arteries from 10 explanted lungs with advanced PAH (5 idiopathic, 5 associated with systemic sclerosis), and 5 donors without lung diseases. Effects of oxfenicine, a FAO inhibitor, on female Sugen 5416-chronic hypoxia (SuHx) rats were studied in vivo using right heart catheterization, and ex vivo using perfused lungs and pulmonary artery ring segments. The impact of pharmacologic (oxfenicine) and genetic (carnitine palmitoyltransferase 1a heterozygosity) FAO suppression was additionally probed in mouse models of and hypoxia-induced PH. Potential mechanisms underlying FAO-induced PH pathogenesis were examined by quantifying ATP and mitochondrial mass in oxfenicine-treated SuHx pulmonary arterial cells, and by assessing pulmonary arterial macrophage infiltration with immunohistochemistry. We found upregulated pulmonary arterial transcription of 26 and 13 FAO genes in idiopathic and systemic sclerosis-associated PAH, respectively. In addition to promoting de-remodeling of pulmonary arteries in SuHx rats, oxfenicine attenuated endothelin-1-induced vasoconstriction. FAO inhibition also conferred modest benefit in the two mouse models of PH. Oxfenicine increased mitochondrial mass in cultured rat pulmonary arterial cells, and decreased the density of perivascular macrophage infiltration in pulmonary arteries of treated SuHx rats. In summary, FAO inhibition attenuated experimental PH, and may be beneficial in human PAH.
代谢失调是动物和人类肺动脉高压（PH）的特征。先前，在受肺动脉高压（PAH）影响的人肺动脉中，尚未评估参与脂肪酸代谢的酶，并且抑制脂肪酸氧化（FAO）如何减轻 PH 仍然不清楚。在 10 个患有晚期 PAH 的离体肺（5 个特发性，5 个与系统性硬化症相关）和 5 个无肺部疾病的供体中，对激光切割的肺动脉中的脂肪酸代谢基因转录进行了定量。在体内使用右心导管术和体外使用灌注肺和肺动脉环段研究了 FAO 抑制剂 oxfenicine 对雌性 Sugen 5416-慢性低氧（SuHx）大鼠的影响。在和缺氧诱导的 PH 的小鼠模型中，还研究了药理（oxfenicine）和遗传（肉碱棕榈酰转移酶 1a 杂合性）FAO 抑制的影响。通过定量 oxfenicine 处理的 SuHx 肺动脉细胞中的 ATP 和线粒体质量，以及通过免疫组织化学评估肺血管巨噬细胞浸润，研究了 FAO 诱导的 PH 发病机制的潜在机制。我们发现，在特发性和系统性硬化症相关的 PAH 中，肺动脉转录上调了 26 和 13 个 FAO 基因。除了促进 SuHx 大鼠肺动脉的去重构外，oxfenicine 还减轻了内皮素-1 引起的血管收缩。FAO 抑制在两种 PH 小鼠模型中也具有适度的益处。Oxfenicine 增加了培养的大鼠肺动脉细胞中的线粒体质量，并减少了治疗后的 SuHx 大鼠肺血管中血管周围巨噬细胞浸润的密度。总之，FAO 抑制减轻了实验性 PH，并且在人类 PAH 中可能有益。
