Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the pulmonary vasculature, cGMP concentrations are regulated in part by a cGMP-dependent phosphodiesterase (PDE), PDE5. Infants with persistent pulmonary hypertension of the newborn (PPHN) are often mechanically ventilated with high oxygen concentrations. The effects of hyperoxia on the developing pulmonary vasculature and PDE5 are largely unknown. Here, we demonstrate that exposure of fetal pulmonary artery smooth muscle cells (FPASMCs) to high levels of oxygen for 24 hours leads to decreased responsiveness to exogenous NO, as determined by a decreased intracellular cGMP response, increased PDE5 mRNA and protein expression, as well as increased PDE5 cGMP hydrolytic activity. We demonstrate that inhibition of PDE5 activity with sildenafil partially rescues cGMP responsiveness to exogenous NO. In FPASMCs, hyperoxia leads to increased oxidative stress without increasing cell death. Treatment of normoxic FPASMCs with H2O2 is sufficient to induce PDE5 expression and activity, suggesting that reactive oxygen species mediate the effects of hyperoxia in FPASMCs. In support of this mechanism, a chemical antioxidant, N-acetyl-cysteine, is sufficient to block the hyperoxia-mediated increase in PDE5 expression and activity and rescue cGMP responsiveness to exogenous NO. Finally, ventilation of healthy neonatal sheep with 100% O2 for 24 hours leads to increased PDE5 protein expression in the resistance pulmonary arteries and increased PDE5 activity in whole lung extracts. These data suggest that PDE5 expression and activity play a critical role in modulating neonatal pulmonary vascular tone in response to common clinical treatments for PPHN, such as oxygen and inhaled NO.
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PMID:Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells. 1799 81

Endothelial progenitor cells (EPCs) play a critical role in the repair of damaged blood vessels and/or in the growth of new ones in ischemic tissues. Elevated levels of oxygen radicals, which accumulate in the ischemic tissue, could compromise the angiogenic potential of EPCs. To determine if oxidative stress alters the angiogenic response of EPCs and to identify possible cellular targets that protect EPCs from the damaging effects of oxidative stress, we have investigated vascular development in embryonic bodies (EBs) under hyperoxic conditions. Murine EBs at differentiaton day 2 were cultured for 3 days under normoxic (21% O(2)) or hyperoxic (60% O(2)) conditions. Hyperoxic EBs showed a moderate reduction in Pecam-1, Vegfr-2, eNOS and Tie2 mRNA levels compared to normoxic EBs. However, immunostaining of hyperoxic EBs with antibodies against PECAM-1 after 1 week recovery at room air revealed a defective vasculature completely deficient in branches, while normoxic EBs developed a normal vascular plexus. Oxygen-induced defective vascular development correlated with a dramatic decrease in soluble guanylyl cyclase, phosphodiesterase (Pde) 4B and Pde4C mRNAs. Oxidative stress did not affect the expression of adenylyl cyclase 6 and Pde5. The abnormal vascular development caused by hyperoxia was reverted by pharmacological treatments that increased cGMP levels, such as 8-bromo-cGMP or 4-{[3',4'-(methylenedioxy)benzyl]amino}-6-methoxyquinazoline, a specific inhibitor of PDE5. These results indicated that oxidative stress inhibits vascular development from EPCs through its effects on levels of cyclic nucleotides and suggested that therapies that target cyclic nucleotide turnover may be useful in protecting vascular repair under oxidative conditions.
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PMID:Cyclic GMP protects endothelial progenitors from oxidative stress. 2149 20

Pulmonary hypertension (PH) occurs in 25 to 35% of premature infants with significant bronchopulmonary dysplasia (BPD). Neonatal mice exposed to 14 days of hyperoxia develop BPD-like lung injury and PH. To determinne the impact of hyperoxia on pulmonary artery (PA) cyclic guanosine monophosphate (cGMP) signaling in a murine model of lung injury and PH, neonatal C57BL/6 mice were placed in room air, 75% O2 for 14 days (chronic hyperoxia [CH]) or 75% O2 for 24 hours, followed by 13 days of room air (acute hyperoxia with recovery [AHR]) with or without sildenafil. At 14 days, mean alveolar area, PA medial wall thickness (MWT), right ventricular hypertrophy (RVH), and vessel density were assessed. PA protein was analyzed for cGMP, soluble guanylate cyclase, and PDE5 activity. CH and AHR mice had RVH, but only CH mice had increased alveolar area and MWT and decreased vessel density. In CH and AHR PAs, soluble guanylate cyclase activity was decreased, and PDE5 activity was increased. In CH mice, sildenafil attenuated MWT and RVH but did not improve mean alveolar area or vessel density. In CH and AHR PAs, sildenafil decreased PDE5 activity and increased cGMP. Our results indicate that prolonged hyperoxia leads to lung injury, PH, RVH, and disrupted PA cGMP signaling. Furthermore, 24 hours of hyperoxia causes RVH and disrupted PA cGMP signaling that persists for 13 days. Sildenafil reduced RVH and restored vascular cGMP signaling but did not attenuate lung injury. Thus, hyperoxia can rapidly disrupt PA cGMP signaling in vivo with sustained effects, and concurrent sildenafil therapy can be protective.
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PMID:Disrupted pulmonary artery cyclic guanosine monophosphate signaling in mice with hyperoxia-induced pulmonary hypertension. 2403 19