Endothelin-1 Depletion of Cartilage Oligomeric Matrix Protein Modulates Pulmonary Artery Superoxide and Iron Metabolism-associated Mitochondrial Heme Biosynthesis.
Endothelin-1 Depletion of Cartilage Oligomeric Matrix Protein Modulates Pulmonary Artery Superoxide and Iron Metabolism-associated Mitochondrial Heme Biosynthesis.
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DOI：
10.1152/ajplung.00534.2020
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发表时间：
2022-08
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影响因子：
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通讯作者：
Hang Yu;Norah Alruwaili;M. Kelly;Bin Zhang;Aijing Liu;Yingqi Wang;Dong Sun;M. Wolin
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作者：
Hang Yu;Norah Alruwaili;M. Kelly;Bin Zhang;Aijing Liu;Yingqi Wang;Dong Sun;M. Wolin
本研究探讨了血红素生物合成相关铁代谢是否通过调节软骨寡聚基质蛋白（COMP）的可用性而受到内皮素-1 （ET1）在肺动脉中的调控。我们对类器官培养的内皮摩擦牛肺动脉（BPA）的研究发现，siRNA或缺氧导致COMP耗竭会增加NOX2和超氧化物，并消耗线粒体SOD2。ET1还以一种可能损害线粒体血红素生物合成的方式增加超氧化物。在本研究中，含ET1 （10nM）的类器官BPA培养增加了线粒体基质和与COMP缺失相关的线粒体额外区域的超氧化物，而COMP （0.5μM）抑制了这些超氧化物的增加。由于线粒体基质超氧化物可以通过降低铁离子可用性和/或铁螯合酶（FECH）来损害原卟啉IX （PpIX）的血红素生物合成，我们研究了ET1、COMP和COMP siRNA对FECH、铁离子可用性指标转铁蛋白受体-1 （TfR1）和可溶性鸟苷酸环化酶（sGC，一种关键的血红素依赖蛋白）表达的影响，以及PpIX （HPLC）和血红素含量的测量。ET1降低FECH、血红素和sGC，升高TfR1和铁。COMP逆转了ET1的这些作用，在没有ET1的情况下，COMP降低了PpIX，增加了血红素。COMP siRNA增加PpIX检测和TfR1表达，降低FECH和sGC表达。双酚a的一氧化氮（精胺NONOate）松弛被ET1抑制，暴露于ET1时，COMP减弱了这种松弛。因此，由ET1或siRNA引起的COMP耗竭调节了肺动脉铁代谢，从而导致血红素生物合成和血红素依赖性cGMP机制的丧失。
This study examines if heme biosynthesis associated iron metabolism is regulated in pulmonary arteries by endothelin-1 (ET1) potentially through modulating Cartilage Oligomeric Matrix Protein (COMP) availability. Our studies in organoid cultured endothelium-rubbed bovine pulmonary arteries (BPA) observed COMP depletion by siRNA or hypoxia increases NOX2 and superoxide, and depletes mitochondrial SOD2. ET1 also increases superoxide in a manner that potentially impairs mitochondrial heme biosynthesis. In this study, organoid culture of BPA with ET1 (10nM) increases superoxide in the mitochondrial matrix and extra mitochondrial regions associated with COMP depletion, and COMP (0.5μM) inhibited these superoxide increases. Since mitochondrial matrix superoxide could impair heme biosynthesis from protoporphyrin IX (PpIX) by decreasing Fe2+ availability and/or ferrochelatase (FECH), we studied ET1, COMP and COMP siRNA effects on the expression of FECH, transferrin receptor-1 (TfR1, an indicator of iron availability) and soluble guanylate cyclase (sGC, a key heme-dependent protein), and on measurements of PpIX (HPLC) and heme content. ET1 decreased FECH, heme and sGC, and increased TfR1 and iron. COMP reversed these effects of ET1, and COMP decreased PpIX and increased heme in the absence of ET1. COMP siRNA increased PpIX detection and TfR1 expression, and decreased the expression of FECH and sGC. Nitric oxide (spermine NONOate) relaxation of BPA was inhibited by ET1, and this was attenuated by COMP during exposure to ET1. Thus, COMP depletion by ET1 or siRNA modulates pulmonary artery iron metabolism, which results in loss of heme biosynthesis and heme-dependent cGMP mechanisms.