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
03/29/2003Pubmed ID
12663260DOI
10.1152/ajpheart.00837.2002Scopus ID
2-s2.0-0038677171 (requires institutional sign-in at Scopus site) 80 CitationsAbstract
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 JrAuthors
Girija Ganesh Konduri MD Chief, Professor in the Pediatrics department at Medical College of WisconsinKirkwood 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 SaltAdenosine 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