Role of oxidative phosphorylation and ATP release in  mediating birth-related pulmonary vasodilation in fetal lambs

Konduri, Girija G.; Mattei, Janine

doi:10.1152/ajpheart.00245.2002

Cited by 30 publications

(33 citation statements)

References 30 publications

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“…The interaction between SOD-2 and iHSP70 in the cytosol is quite unique and differs from eNOS-HSP90 interaction, which increases eNOS activity (34). Our observation specific to SOD2-iHSP70 association is that, in the cytosol, this association appears to increase SOD-2 transport to the mitochondria.…”

Section: Discussionmentioning

confidence: 55%

“…This study was approved by the Institutional Animal Care and Use Committee of the Medical College of Wisconsin and conformed to NIH guidelines for animal use in research. Constriction of fetal ductus arteriosus was performed at 128 Ϯ 2 days of gestation (term ϭ 144 days) as we described previously (33,34). Control fetal lambs had thoracotomy performed without constriction of the ductus arteriosus.…”

Section: Methodsmentioning

confidence: 99%

“…PAECs were isolated and characterized using techniques we described previously (33,34). PAEC isolated from control (normal) and hypertensive fetal lambs were cultured in DMEM with 20% FCS at 37°C in room air and 5% CO 2.…”

Section: Methodsmentioning

confidence: 99%

“…After incubation, excess PFT-or DMSO was removed, and treated PA rings were incubated in 2-ml tissue baths, where the pH and PO2 were normalized for all rings. PA ring tension was measured by wire myography using standard techniques, as we described previously (2,33,34). PA rings were preconstricted with 10 Ϫ7 M norepinephrine, and the relaxation response to log doses of ATP (a NOS agonist) and/or S-nitroso-N-acetyl-penicillamine (SNAP, an Ṅ O donor) in the presence/absence of 10 Ϫ12 M Mito-Q (a mitochondrial-targeted O2 ·Ϫ scavenger) were measured.…”

Section: -Oh-mito-ementioning

confidence: 99%

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Inducible HSP70 regulates superoxide dismutase-2 and mitochondrial oxidative stress in the endothelial cells from developing lungs

Afolayan

Teng

Eis

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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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-(PFT-, 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 2 facilitated the mitochondrial import of SOD-2, increased SOD-2 activity, and decreased the mitochondrial superoxide (O 2 ·Ϫ ) 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 2 ·Ϫ 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-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 2 ·Ϫ scavenger, restored the relaxation response in PA rings pretreated with PFT-. 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.persistent pulmonary hypertension of the newborn; pulmonary artery endothelium; oxidative stress; vasodilation; nitric oxide OXIDATIVE STRESS PLAYS A KEY ROLE in the pathogenesis of pulmonary hypertension (14, 41a). Persistent pulmonary hypertension of the newborn (PPHN) is associated with increased generation of reactive oxygen species (ROS), including superoxide radical (O 2 ·Ϫ ) (10). ROS induces pulmonary vascular remodeling, which leads to increased vascular resistance and impaired pulmonary vasodilation in PPHN (46). Studies in a fetal lamb model of PPHN induced by prenatal constriction of the ductus arteriosus have previously identified increased NA-DPH oxidase activity and uncoupling of endothelial nitric oxide synthase (eNOS) as the major sources of O 2 ·Ϫ in the cytosol (10,33,36 ·Ϫ generation in the mitochondria, which in turn plays a major role in the toxicity of hyperoxia (44). Newborns are at risk of experiencing oxidative stress because O 2 concentrations increase by several times at birth compared with in utero environment. Adaptive increases in cellular antioxidant defenses, particularly superoxide dismutases (SODs), du...

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Section: Discussionmentioning

confidence: 55%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: -Oh-mito-ementioning

confidence: 99%

See 2 more Smart Citations

Inducible HSP70 regulates superoxide dismutase-2 and mitochondrial oxidative stress in the endothelial cells from developing lungs

Afolayan

Teng

Eis

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

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“…Endothelium derived nitric oxide (NO) plays a major role in this birth-related transition (1,2). Oxygen, adenosine triphosphate (ATP), and estrogen are important physiologic signals for activation of endothelial NO synthase (eNOS) at birth (2)(3)(4)(5). Endothelium also regulates vascular tone with the release of potent vasoconstrictors, such as endothelin (6).…”

mentioning

confidence: 99%

Betamethasone Attenuates Oxidant Stress in Endothelial Cells from Fetal Lambs with Persistent Pulmonary Hypertension

2008

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ABSTRACT:We investigated the effects of betamethasone on oxidative stress and impaired vasodilation in a lamb model of persistent pulmonary hypertension (PPHN). We treated pregnant ewes following fetal ductal ligation with betamethasone or saline for 48 h before delivery. Response of fetal pulmonary arteries to nitric oxide synthase (NOS) agonist adenosine triphosphate (ATP) and nitric oxide (NO) donor, s-nitroso-n-acetyl-penicillamine (SNAP) was determined in tissue bath. Pulmonary artery endothelial cells (PAEC) from fetal lambs with ductal ligation or sham ligation were treated with betamethasone or its vehicle for 48 h. Expression of endothelial NOS (eNOS), endothelin, endothelin-B (ET-B) receptor, and CuZn-and Mn-superoxide dismutase (SOD) in PAEC was studied. Intracellular cGMP and superoxide levels and interaction of eNOS with heat shock protein 90 (Hsp90) were determined in PAEC. Antenatal betamethasone improved the relaxation response of pulmonary arteries to ATP and SNAP in PPHN. PPHN was associated with decreases in eNOS and ET-B receptor and increase in preproendothelin mRNA levels. Betamethasone decreased preproendothelin mRNA and ET-1 pro-peptide levels and increased eNOS and MnSOD protein levels in PPHN. Betamethasone reversed the increased superoxide/decreased cGMP levels and restored Hsp90-eNOS interactions in PPHN. Betamethasone reduces oxidative stress and improves response of pulmonary arteries to vasodilators in lambs with PPHN. T he pulmonary vascular resistance (PVR) in the fetus undergoes a dramatic decrease at birth with the initiation of ventilation and oxygenation. Endothelium derived nitric oxide (NO) plays a major role in this birth-related transition (1,2). Oxygen, adenosine triphosphate (ATP), and estrogen are important physiologic signals for activation of endothelial NO synthase (eNOS) at birth (2-5). Endothelium also regulates vascular tone with the release of potent vasoconstrictors, such as endothelin (6). Endothelin causes vasoconstriction and has biologic effects on NO release and smooth muscle growth (7,8). Failure of PVR to decrease at birth results in persistent pulmonary hypertension of newborn (PPHN) and impaired oxygenation. PPHN is associated with decreased NO release and increased endothelin production, both of which contribute to impaired pulmonary vasodilation (9,10). Recent studies in the fetal lamb model of PPHN induced by prenatal ligation of ductus arteriosus demonstrated a role for increased oxidative stress in the impaired pulmonary vasodilation (11,12). Both NADPH oxidase and uncoupled eNOS contribute to the increased ROS in this model (11,12). A coordinated regulation of endothelin and eNOS gene expression has been demonstrated in the ductal ligation model (13). Endothelin increases oxidant stress in PPHN (8) and inhibition of endothelin receptor-A attenuates pulmonary hypertension in fetal lambs (14). PPHN is also associated with a decrease in total superoxide dismutase (SOD) activity in pulmonary arteries (11). Thus, the impaired vasodilation in PPHN is a...

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Hypoxic Pulmonary Vasoconstriction: Heterogeneity

Dawson

Hypoxic Pulmonary Vasoconstriction

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Role of oxidative phosphorylation and ATP release in mediating birth-related pulmonary vasodilation in fetal lambs

Cited by 30 publications

References 30 publications

Inducible HSP70 regulates superoxide dismutase-2 and mitochondrial oxidative stress in the endothelial cells from developing lungs

Inducible HSP70 regulates superoxide dismutase-2 and mitochondrial oxidative stress in the endothelial cells from developing lungs

Betamethasone Attenuates Oxidant Stress in Endothelial Cells from Fetal Lambs with Persistent Pulmonary Hypertension

Hypoxic Pulmonary Vasoconstriction: Heterogeneity

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