Centre de Recherche Cardio-thoracique de Bordeaux, U1045, MRGM, Functional Genomics Center (CGFB), CIC 1401, CELLOMET, Univ-Bordeaux, Bordeaux, France.
Centre de Recherche Cardio-thoracique de Bordeaux, U1045, U1211, CIC 1401, INSERM, Bordeaux, France.
Eur Respir J. 2021 Nov 25;58(5). doi: 10.1183/13993003.04252-2020. Print 2021 Nov.
Bronchial smooth muscle (BSM) remodelling in asthma is related to an increased mitochondrial biogenesis and enhanced BSM cell proliferation in asthma. Since mitochondria produce the highest levels of cellular energy and fatty acid β-oxidation is the most powerful way to produce ATP, we hypothesised that, in asthmatic BSM cells, energetic metabolism is shifted towards the β-oxidation of fatty acids.
We aimed to characterise BSM cell metabolism in asthma both and to identify a novel target for reducing BSM cell proliferation.
21 asthmatic and 31 non-asthmatic patients were enrolled. We used metabolomic and proteomic approaches to study BSM cells. Oxidative stress, ATP synthesis, fatty acid endocytosis, metabolite production, metabolic capabilities, mitochondrial networks, cell proliferation and apoptosis were assessed on BSM cells. Fatty acid content was assessed using matrix-assisted laser desorption/ionisation spectrometry imaging.
Asthmatic BSM cells were characterised by an increased rate of mitochondrial respiration with a stimulated ATP production and mitochondrial β-oxidation. Fatty acid consumption was increased in asthmatic BSM both and . Proteome remodelling of asthmatic BSM occurred two canonical mitochondrial pathways. The levels of carnitine palmitoyl transferase (CPT)2 and low-density lipoprotein (LDL) receptor, which internalise fatty acids through mitochondrial and cell membranes, respectively, were both increased in asthmatic BSM cells. Blocking CPT2 or LDL receptor drastically and specifically reduced asthmatic BSM cell proliferation.
This study demonstrates a metabolic switch towards mitochondrial β-oxidation in asthmatic BSM and identifies fatty acid metabolism as a new key target to reduce BSM remodelling in asthma.
哮喘中的支气管平滑肌（BSM）重塑与线粒体生物发生增加以及哮喘中 BSM 细胞增殖增强有关。由于线粒体产生细胞能量的水平最高，而脂肪酸β-氧化是产生 ATP 的最有效方式，我们假设在哮喘的 BSM 细胞中，能量代谢向脂肪酸的β-氧化转移。
我们旨在研究哮喘中 BSM 细胞的代谢特征，并确定减少 BSM 细胞增殖的新靶点。
纳入 21 例哮喘患者和 31 例非哮喘患者。我们使用代谢组学和蛋白质组学方法研究 BSM 细胞。评估 BSM 细胞的氧化应激、ATP 合成、脂肪酸内吞、代谢产物产生、代谢能力、线粒体网络、细胞增殖和凋亡。使用基质辅助激光解吸/电离质谱成像评估脂肪酸含量。
哮喘 BSM 细胞的特征是线粒体呼吸率增加，同时刺激 ATP 产生和线粒体β-氧化。哮喘 BSM 中的脂肪酸消耗增加。哮喘 BSM 的蛋白质组重塑发生在两个经典的线粒体途径中。肉碱棕榈酰转移酶（CPT）2 和低密度脂蛋白（LDL）受体的水平增加，它们分别通过线粒体和细胞膜内化脂肪酸，在哮喘 BSM 细胞中均增加。阻断 CPT2 或 LDL 受体可显著和特异性地减少哮喘 BSM 细胞增殖。
本研究表明哮喘 BSM 中存在向线粒体β-氧化的代谢转变，并确定脂肪酸代谢是减少哮喘中 BSM 重塑的新关键靶点。
