Protein complex formation with heat shock protein 90 in chronic hypoxia-induced pulmonary hypertension in newborn piglets

Candice D. Fike, Sandra L. Pfister, James C. Slaughter, Mark R. Kaplowitz, Yongmei Zhang, Heng Zeng, Naila Rashida Frye, Judy L. Aschner

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Aberrant interactions between heat shock protein (Hsp)90 and its client proteins could contribute to pulmonary hypertension. We tested the hypotheses that 1) the interaction between Hsp90 and its known client protein, endothelial nitric oxide synthase (eNOS), is impaired in pulmonary resistance arteries (PRAs) from piglets with pulmonary hypertension caused by exposure to 3 or 10 days of hypoxia and 2) Hsp90 interacts with the prostanoid pathway proteins prostacyclin synthase (PGIS) and/or thromboxane synthase (TXAS).Wealso determined whether Hsp90 antagonism with geldanamycin alters the agonistinduced synthesis of prostacyclin and thromboxane or alters PRA responses to these prostaglandin metabolites. Compared with normoxic piglets, less eNOS coimmunoprecipitated with Hsp90 in PRAs from hypoxic piglets. Despite reduced Hsp90-eNOS interactions, dilation to ACh was enhanced in geldanamycin-treated PRAs from hypoxic, but not normoxic, piglets. In PRAs from all groups of piglets, PGIS and TXAS coimmunoprecipitated with Hsp90. Geldanamycin reduced the ACh-induced synthesis of prostacyclin and thromboxane and altered responses to the thromboxane mimetic U-46619 in PRAs from all groups. Although geldanamycin enhanced responses to prostacyclin in PRAs from both groups of hypoxic piglets, geldanamycin had no effect on prostacyclin responses in PRAs from either group of normoxic piglets. Our findings indicate that Hsp90 influences both prostanoid and eNOS signaling in the pulmonary circulation of newborn piglets and that the impact of pharmacological inhibition of Hsp90 on these signaling pathways is altered during exposure to chronic hypoxia.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume299
Issue number4
DOIs
StatePublished - Oct 2010
Externally publishedYes

Fingerprint

HSP90 Heat-Shock Proteins
Pulmonary Hypertension
Pulmonary Artery
Thromboxanes
Nitric Oxide Synthase Type III
Epoprostenol
Proteins
Prostaglandins
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Pulmonary Circulation
Hypoxia
Dilatation
geldanamycin
Pharmacology

Keywords

  • Arachidonic acid metabolites
  • Endothelial nitric oxide synthase
  • Prostacyclin synthase
  • Prostanoids
  • Thromboxane synthase

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Protein complex formation with heat shock protein 90 in chronic hypoxia-induced pulmonary hypertension in newborn piglets. / Fike, Candice D.; Pfister, Sandra L.; Slaughter, James C.; Kaplowitz, Mark R.; Zhang, Yongmei; Zeng, Heng; Frye, Naila Rashida; Aschner, Judy L.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 299, No. 4, 10.2010.

Research output: Contribution to journalArticle

Fike, Candice D. ; Pfister, Sandra L. ; Slaughter, James C. ; Kaplowitz, Mark R. ; Zhang, Yongmei ; Zeng, Heng ; Frye, Naila Rashida ; Aschner, Judy L. / Protein complex formation with heat shock protein 90 in chronic hypoxia-induced pulmonary hypertension in newborn piglets. In: American Journal of Physiology - Heart and Circulatory Physiology. 2010 ; Vol. 299, No. 4.
@article{349085856e8d4928b99a68dca19ca3f3,
title = "Protein complex formation with heat shock protein 90 in chronic hypoxia-induced pulmonary hypertension in newborn piglets",
abstract = "Aberrant interactions between heat shock protein (Hsp)90 and its client proteins could contribute to pulmonary hypertension. We tested the hypotheses that 1) the interaction between Hsp90 and its known client protein, endothelial nitric oxide synthase (eNOS), is impaired in pulmonary resistance arteries (PRAs) from piglets with pulmonary hypertension caused by exposure to 3 or 10 days of hypoxia and 2) Hsp90 interacts with the prostanoid pathway proteins prostacyclin synthase (PGIS) and/or thromboxane synthase (TXAS).Wealso determined whether Hsp90 antagonism with geldanamycin alters the agonistinduced synthesis of prostacyclin and thromboxane or alters PRA responses to these prostaglandin metabolites. Compared with normoxic piglets, less eNOS coimmunoprecipitated with Hsp90 in PRAs from hypoxic piglets. Despite reduced Hsp90-eNOS interactions, dilation to ACh was enhanced in geldanamycin-treated PRAs from hypoxic, but not normoxic, piglets. In PRAs from all groups of piglets, PGIS and TXAS coimmunoprecipitated with Hsp90. Geldanamycin reduced the ACh-induced synthesis of prostacyclin and thromboxane and altered responses to the thromboxane mimetic U-46619 in PRAs from all groups. Although geldanamycin enhanced responses to prostacyclin in PRAs from both groups of hypoxic piglets, geldanamycin had no effect on prostacyclin responses in PRAs from either group of normoxic piglets. Our findings indicate that Hsp90 influences both prostanoid and eNOS signaling in the pulmonary circulation of newborn piglets and that the impact of pharmacological inhibition of Hsp90 on these signaling pathways is altered during exposure to chronic hypoxia.",
keywords = "Arachidonic acid metabolites, Endothelial nitric oxide synthase, Prostacyclin synthase, Prostanoids, Thromboxane synthase",
author = "Fike, {Candice D.} and Pfister, {Sandra L.} and Slaughter, {James C.} and Kaplowitz, {Mark R.} and Yongmei Zhang and Heng Zeng and Frye, {Naila Rashida} and Aschner, {Judy L.}",
year = "2010",
month = "10",
doi = "10.1152/ajpheart.01207.2009",
language = "English (US)",
volume = "299",
journal = "American Journal of Physiology - Renal Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "4",

}

TY - JOUR

T1 - Protein complex formation with heat shock protein 90 in chronic hypoxia-induced pulmonary hypertension in newborn piglets

AU - Fike, Candice D.

AU - Pfister, Sandra L.

AU - Slaughter, James C.

AU - Kaplowitz, Mark R.

AU - Zhang, Yongmei

AU - Zeng, Heng

AU - Frye, Naila Rashida

AU - Aschner, Judy L.

PY - 2010/10

Y1 - 2010/10

N2 - Aberrant interactions between heat shock protein (Hsp)90 and its client proteins could contribute to pulmonary hypertension. We tested the hypotheses that 1) the interaction between Hsp90 and its known client protein, endothelial nitric oxide synthase (eNOS), is impaired in pulmonary resistance arteries (PRAs) from piglets with pulmonary hypertension caused by exposure to 3 or 10 days of hypoxia and 2) Hsp90 interacts with the prostanoid pathway proteins prostacyclin synthase (PGIS) and/or thromboxane synthase (TXAS).Wealso determined whether Hsp90 antagonism with geldanamycin alters the agonistinduced synthesis of prostacyclin and thromboxane or alters PRA responses to these prostaglandin metabolites. Compared with normoxic piglets, less eNOS coimmunoprecipitated with Hsp90 in PRAs from hypoxic piglets. Despite reduced Hsp90-eNOS interactions, dilation to ACh was enhanced in geldanamycin-treated PRAs from hypoxic, but not normoxic, piglets. In PRAs from all groups of piglets, PGIS and TXAS coimmunoprecipitated with Hsp90. Geldanamycin reduced the ACh-induced synthesis of prostacyclin and thromboxane and altered responses to the thromboxane mimetic U-46619 in PRAs from all groups. Although geldanamycin enhanced responses to prostacyclin in PRAs from both groups of hypoxic piglets, geldanamycin had no effect on prostacyclin responses in PRAs from either group of normoxic piglets. Our findings indicate that Hsp90 influences both prostanoid and eNOS signaling in the pulmonary circulation of newborn piglets and that the impact of pharmacological inhibition of Hsp90 on these signaling pathways is altered during exposure to chronic hypoxia.

AB - Aberrant interactions between heat shock protein (Hsp)90 and its client proteins could contribute to pulmonary hypertension. We tested the hypotheses that 1) the interaction between Hsp90 and its known client protein, endothelial nitric oxide synthase (eNOS), is impaired in pulmonary resistance arteries (PRAs) from piglets with pulmonary hypertension caused by exposure to 3 or 10 days of hypoxia and 2) Hsp90 interacts with the prostanoid pathway proteins prostacyclin synthase (PGIS) and/or thromboxane synthase (TXAS).Wealso determined whether Hsp90 antagonism with geldanamycin alters the agonistinduced synthesis of prostacyclin and thromboxane or alters PRA responses to these prostaglandin metabolites. Compared with normoxic piglets, less eNOS coimmunoprecipitated with Hsp90 in PRAs from hypoxic piglets. Despite reduced Hsp90-eNOS interactions, dilation to ACh was enhanced in geldanamycin-treated PRAs from hypoxic, but not normoxic, piglets. In PRAs from all groups of piglets, PGIS and TXAS coimmunoprecipitated with Hsp90. Geldanamycin reduced the ACh-induced synthesis of prostacyclin and thromboxane and altered responses to the thromboxane mimetic U-46619 in PRAs from all groups. Although geldanamycin enhanced responses to prostacyclin in PRAs from both groups of hypoxic piglets, geldanamycin had no effect on prostacyclin responses in PRAs from either group of normoxic piglets. Our findings indicate that Hsp90 influences both prostanoid and eNOS signaling in the pulmonary circulation of newborn piglets and that the impact of pharmacological inhibition of Hsp90 on these signaling pathways is altered during exposure to chronic hypoxia.

KW - Arachidonic acid metabolites

KW - Endothelial nitric oxide synthase

KW - Prostacyclin synthase

KW - Prostanoids

KW - Thromboxane synthase

UR - http://www.scopus.com/inward/record.url?scp=77958025198&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77958025198&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.01207.2009

DO - 10.1152/ajpheart.01207.2009

M3 - Article

VL - 299

JO - American Journal of Physiology - Renal Physiology

JF - American Journal of Physiology - Renal Physiology

SN - 1931-857X

IS - 4

ER -