{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:08:40Z","timestamp":1791896920202,"version":"4.3.4"},"reference-count":51,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2014,2,15]]},"abstract":"<jats:p> Superoxide dismutase 2 (SOD-2) is synthesized in the cytosol and imported into the mitochondrial matrix, where it is activated and functions as the primary antioxidant for cellular respiration. The specific mechanisms that target SOD-2 to the mitochondria remain unclear. We hypothesize that inducible heat shock protein 70 (iHSP70) targets SOD-2 to the mitochondria via a mechanism facilitated by ATP, and this process is impaired in persistent pulmonary hypertension of the newborn (PPHN). We observed that iHSP70 interacts with SOD-2 and targets SOD-2 to the mitochondria. Interruption of iHSP70-SOD-2 interaction with 2-phenylethylenesulfonamide-\u03bc (PFT-\u03bc, a specific inhibitor of substrate binding to iHSP70 COOH terminus) and siRNA-mediated knockdown of iHSP70 expression disrupted SOD-2 transport to mitochondria. Increasing intracellular ATP levels by stimulation of respiration with CaCl<jats:sub>2<\/jats:sub> facilitated the mitochondrial import of SOD-2, increased SOD-2 activity, and decreased the mitochondrial superoxide (O<jats:sub>2<\/jats:sub><jats:sup>\u00b7\u2212<\/jats:sup>) levels in PPHN pulmonary artery endothelial cells (PAEC) by promoting iHSP70-SOD-2 dissociation at the outer mitochondrial membrane. In contrast, oligomycin, an inhibitor of mitochondrial ATPase, decreased SOD-2 expression and activity and increased O<jats:sub>2<\/jats:sub><jats:sup>\u00b7\u2212<\/jats:sup> levels in the mitochondria of control PAEC. The basal ATP levels and degree of iHSP70-SOD-2 dissociation were lower in PPHN PAEC and lead to increased SOD-2 degradation in cytosol. In normal pulmonary arteries (PA), PFT-\u03bc impaired the relaxation response of PA rings in response to nitric oxide (NO) donor, S-nitroso- N-acetyl-penicillamine. Pretreatment with Mito-Q, a mitochondrial targeted O<jats:sub>2<\/jats:sub><jats:sup>\u00b7\u2212<\/jats:sup> scavenger, restored the relaxation response in PA rings pretreated with PFT-\u03bc. Our observations suggest that iHSP70 chaperones SOD-2 to the mitochondria. Impaired SOD-2-iHSP70 dissociation decreases SOD-2 import and contributes to mitochondrial oxidative stress in PPHN. <\/jats:p>","DOI":"10.1152\/ajplung.00264.2013","type":"journal-article","created":{"date-parts":[[2013,12,28]],"date-time":"2013-12-28T03:02:39Z","timestamp":1388199759000},"page":"L351-L360","source":"Crossref","is-referenced-by-count":42,"title":["Inducible HSP70 regulates superoxide dismutase-2 and mitochondrial oxidative stress in the endothelial cells from developing lungs"],"prefix":"10.1152","volume":"306","author":[{"given":"Adeleye J.","family":"Afolayan","sequence":"first","affiliation":[{"name":"Departments of Pediatrics,"},{"name":"Cardiovascular Research Center, and"},{"name":"Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru-Jeng","family":"Teng","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics,"},{"name":"Cardiovascular Research 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