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1 Department of Pediatrics, Medical College of WI, Milwaukee, WI, USA; Department of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Pediatrics, Medical College of WI, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: gkonduri{at}mcw.edu.
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 nitric oxide synthase (eNOS) impairs NO release and vasodilation in PPHN. Response to NOS agonist, ATP was 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 vasodilator response of control arteries to ATP was attenuated by N-nitro-l-arginine methylester (L-NAME), a NOS antagonist and geldanamycin, an inhibitor of Hsp90-eNOS interactions. The attenuated response to ATP observed in PPHN was improved by pre-treatment of vessels with L-NAME or Tiron, 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 impaired NO release and vasodilation in the ductal ligation model of PPHN.
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