Decreased association of HSP90 impairs endothelial nitric oxide synthase in fetal lambs with persistent pulmonary hypertension.
Persistent pulmonary hypertension of newborn (PPHN) is associated with decreased nitric oxide (NO) release and impaired pulmonary vasodilation. We investigated the hypothesis that decreased association of heat shock protein 90 (HSP90) with endothelial NO synthase (eNOS) impairs NO release and vasodilation in PPHN. The responses to the NOS agonist ATP were investigated in fetal lambs with PPHN induced by prenatal ligation of ductus arteriosus, and in sham ligation controls. ATP caused dose-dependent vasodilation in control pulmonary resistance arteries, and this response was attenuated in PPHN vessels. The response of control pulmonary arteries to ATP was attenuated by NG-nitro-l-arginine methyl ester (l-NAME), a NOS antagonist, and geldanamycin, an inhibitor of HSP90-eNOS interaction. The attenuated response to ATP observed in PPHN was improved by pretreatment of vessels with l-NAME or 4,5-dihydroxy-1,3-benzene-disulfonate, a superoxide scavenger. Pulmonary arteries from PPHN lambs had decreased basal levels of HSP90 in association with eNOS. Association of HSP90 with eNOS and NO release increased in response to ATP in control pulmonary artery endothelial cells, but not in cells from PPHN lambs. Decreased HSP90-eNOS interactions may contribute to the impaired NO release and vasodilation observed in the ductal ligation model of PPHN.
Konduri
Girija G
GG
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA. gkonduri@mcw.edu
Ou
Jingsong
J
Shi
Yang
Y
Pritchard
Kirkwood A
KA
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001784:Blood Gas Analysis; D002469:Cell Separation; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005333:Fetus / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D007202:Indicators and Reagents; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D011247:Pregnancy; D011651:Pulmonary Artery / Q000166:cytology / Q000502:physiology; D012756:Sheep; D014655:Vascular Resistance
D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D007202:Indicators and Reagents; D009569:Nitric Oxide; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester