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Decreased association of HSP90 impairs endothelial nitric oxide synthase in fetal lambs with persistent pulmonary hypertension. Am J Physiol Heart Circ Physiol 2003 Jul;285(1):H204-11

Date

03/29/2003

Pubmed ID

12663260

DOI

10.1152/ajpheart.00837.2002

Scopus ID

2-s2.0-0038677171   75 Citations

Abstract

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.

Author List

Konduri GG, Ou J, Shi Y, Pritchard KA Jr

Authors

Girija Ganesh Konduri MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
Adenosine Triphosphate
Animals
Blood Gas Analysis
Cell Separation
Cells, Cultured
Enzyme Inhibitors
Female
Fetus
HSP90 Heat-Shock Proteins
Hydrogen-Ion Concentration
Hypertension, Pulmonary
Indicators and Reagents
NG-Nitroarginine Methyl Ester
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type III
Pregnancy
Pulmonary Artery
Sheep
Vascular Resistance
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a