Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension
Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension
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DOI：
10.1152/ajplung.00155.2014
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发表时间：
2015-04-01
影响因子：
4.9
通讯作者：
Wolin, Michael S.
中科院分区：
文献类型：
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作者：
Alhawaj, Raed;Patel, Dhara;Wolin, Michael S.
本研究探讨了δ-氨基乙酰丙酸（ALA）对血红素生物合成的调节如何防止21天缺氧（10%氧气）诱导的小鼠肺动脉高压以及用牛肺动脉（BPA）与缺氧和肺动脉高压介质内皮素-1（ET-1）培养24小时的类器官的影响，重点是超氧化物的变化和信号转导和转录激活因子3（STAT 3）的src激酶磷酸化对micro-RNA 204（miR 204）表达的调节。用ALA治疗小鼠减轻了肺动脉高压（通过肺动脉瓣的回波多普勒血流以及右心室收缩压和右心室肥大的直接测量来评估）、肺动脉超氧化物的增加（通过光泽精检测）以及肺miR 204和线粒体超氧化物歧化酶（SOD 2）表达的降低。ALA处理BPA减弱了ET-1诱导的线粒体超氧化物（通过MitoSox检测）、STAT 3磷酸化的增加以及miR 204和SOD 2表达的降低。由于ALA增加BPA原卟啉IX（鸟苷酸环化酶的刺激剂）和cGMP介导的蛋白激酶G（PKG）活性，因此检查了PKG激活剂8-溴-cGMP的作用，发现也减弱了ET-1诱导的超氧化物的增加。ET-1增加超氧化物的产生和原卟啉IX荧光的检测，表明氧化条件可能会损害亚铁螯合酶血红素的生物合成。然而，慢性缺氧实际上增加小鼠肺动脉中的亚铁螯合酶活性。因此，增加线粒体超氧化物和氧化剂作用的因子的逆转可能是ALA在肺动脉高压中的有益作用的因子，所述线粒体超氧化物和氧化剂作用潜在地影响与miR 204表达相关的重构信号传导，并且可能影响通过亚铁螯合酶反应生物合成血红素所需的铁可用性。
This study examines how heme biosynthesis modulation with delta-aminolevulinic acid (ALA) potentially functions to prevent 21-day hypoxia (10% oxygen)-induced pulmonary hypertension in mice and the effects of 24-h organoid culture with bovine pulmonary arteries (BPA) with the hypoxia and pulmonary hypertension mediator endothelin-1 (ET-1), with a focus on changes in superoxide and regulation of micro-RNA 204 (miR204) expression by src kinase phosphorylation of signal transducer and activator of transcription-3 (STAT3). The treatment of mice with ALA attenuated pulmonary hypertension (assessed through echo Doppler flow of the pulmonary valve, and direct measurements of right ventricular systolic pressure and right ventricular hypertrophy), increases in pulmonary arterial superoxide (detected by lucigenin), and decreases in lung miR204 and mitochondrial superoxide dismutase (SOD2) expression. ALA treatment of BPA attenuated ET-1-induced increases in mitochondrial superoxide (detected by MitoSox), STAT3 phosphorylation, and decreases in miR204 and SOD2 expression. Because ALA increases BPA protoporphyrin IX (a stimulator of guanylate cyclase) and cGMP-mediated protein kinase G (PKG) activity, the effects of the PKG activator 8-bromo-cGMP were examined and found to also attenuate the ET-1-induced increase in superoxide. ET-1 increased superoxide production and the detection of protoporphyrin IX fluorescence, suggesting oxidant conditions might impair heme biosynthesis by ferrochelatase. However, chronic hypoxia actually increased ferrochelatase activity in mouse pulmonary arteries. Thus, a reversal of factors increasing mitochondrial superoxide and oxidant effects that potentially influence remodeling signaling related to miR204 expression and perhaps iron availability needed for the biosynthesis of heme by the ferrochelatase reaction could be factors in the beneficial actions of ALA in pulmonary hypertension.