Endothelin-1 Depletion of Cartilage Oligomeric Matrix Protein Modulates Pulmonary Artery Superoxide and Iron Metabolism-Associated Mitochondrial Heme Biosynthesis
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 (BPAs) 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 (10 nM) increases superoxide in the mitochondrial matrix and extramitochondrial regions associated with COMP depletion, and COMP (0.5 μM) inhibited these superoxide increases. As mitochondrial matrix superoxide could impair heme biosynthesis from protoporphyrin IX (PpIX) by decreasing Fe 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.
Yu, H., Alruwaili, N., Kelly, M. R., Zhang, B., Liu, A., Wang, Y., Sun, D., & Wolin, M. S. (2022). Endothelin-1 Depletion of Cartilage Oligomeric Matrix Protein Modulates Pulmonary Artery Superoxide and Iron Metabolism-Associated Mitochondrial Heme Biosynthesis. https://doi.org/10.1152/ajplung.00534.2020