Betamethasone attenuates oxidant stress in endothelial cells from fetal lambs with persistent pulmonary hypertension.
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 prepro-endothelin mRNA levels. Betamethasone decreased prepro-endothelin 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.
Chandrasekar
Indira
I
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53201, USA.
Eis
Annie
A
Konduri
Girija G
GG
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001623:Betamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004373:Ductus Arteriosus / Q000601:surgery; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000196:embryology / Q000378:metabolism / Q000503:physiopathology; D008026:Ligation; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism / Q000503:physiopathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011247:Pregnancy; D011651:Pulmonary Artery / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D012756:Sheep; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology
D000975:Antioxidants; D016232:Endothelins; D018841:HSP90 Heat-Shock Proteins; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D014665:Vasodilator Agents; D013481:Superoxides; D026423:S-Nitroso-N-Acetylpenicillamine; D000255:Adenosine Triphosphate; D001623:Betamethasone; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D006152:Cyclic GMP