Activation of Hsp90-eNOS and increased NO generation attenuate respiration of hypoxia-treated endothelial cells

Tennille Presley, Kaushik Vedam, Murugesan Velayutham, Jay L. Zweier, Govindasamy Ilangovan

Research output: Contribution to journalArticle

Abstract

Hypoxia induces various adoptive signaling in cells that can cause several physiological changes. In the present work, we have observed that exposure of bovine aortic endothelial cells (BAECs) to extreme hypoxia (1-5% O2) attenuates cellular respiration by a mechanism involving heat shock protein 90 (Hsp90) and endothelial nitric oxide (NO) synthase (eNOS), so that the cells are conditioned to consume less oxygen and survive in prolonged hypoxic conditions. BAECs, exposed to 1% O2, showed a reduced respiration compared with 21% O2-maintained cells. Western blot analysis showed an increase in the association of Hsp90-eNOS and enhanced NO generation on hypoxia exposure, whereas there was no significant accumulation of hypoxia-inducible factor-1α (HIF-1α). The addition of inhibitors of Hsp90, phosphatidylinositol 3-kinase, and NOS significantly alleviated this hypoxia-induced attenuation of respiration. Thus we conclude that hypoxia-induced excess NO and its derivatives such as ONOO- cause inhibition of the electron transport chain and attenuate O2 demand, leading to cell survival at extreme hypoxia. More importantly, such an attenuation is found to be independent of HIF-1α, which is otherwise thought to be the key regulator of respiration in hypoxia-exposed cells, through a nonphosphorylative glycolytic pathway. The present mechanistic insight will be helpful to understand the difference in the magnitude of endothelial dysfunction.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume295
Issue number5
DOIs
StatePublished - Nov 2008
Externally publishedYes

Fingerprint

HSP90 Heat-Shock Proteins
Nitric Oxide Synthase Type III
Nitric Oxide Synthase
Nitric Oxide
Respiration
Endothelial Cells
Hypoxia-Inducible Factor 1
Phosphatidylinositol 3-Kinase
Cell Respiration
Cell Hypoxia
Electron Transport
Hypoxia
Cell Survival
Western Blotting
Oxygen

Keywords

  • Electron paramagnetic resonance oximetry
  • Endothelial nitric oxide synthase
  • Heat shock protein 90
  • Oxygen

ASJC Scopus subject areas

  • Cell Biology
  • Physiology

Cite this

Activation of Hsp90-eNOS and increased NO generation attenuate respiration of hypoxia-treated endothelial cells. / Presley, Tennille; Vedam, Kaushik; Velayutham, Murugesan; Zweier, Jay L.; Ilangovan, Govindasamy.

In: American Journal of Physiology - Cell Physiology, Vol. 295, No. 5, 11.2008.

Research output: Contribution to journalArticle

Presley, Tennille ; Vedam, Kaushik ; Velayutham, Murugesan ; Zweier, Jay L. ; Ilangovan, Govindasamy. / Activation of Hsp90-eNOS and increased NO generation attenuate respiration of hypoxia-treated endothelial cells. In: American Journal of Physiology - Cell Physiology. 2008 ; Vol. 295, No. 5.
@article{0ba6ead52ca3464195345dc3dfe6bd3d,
title = "Activation of Hsp90-eNOS and increased NO generation attenuate respiration of hypoxia-treated endothelial cells",
abstract = "Hypoxia induces various adoptive signaling in cells that can cause several physiological changes. In the present work, we have observed that exposure of bovine aortic endothelial cells (BAECs) to extreme hypoxia (1-5{\%} O2) attenuates cellular respiration by a mechanism involving heat shock protein 90 (Hsp90) and endothelial nitric oxide (NO) synthase (eNOS), so that the cells are conditioned to consume less oxygen and survive in prolonged hypoxic conditions. BAECs, exposed to 1{\%} O2, showed a reduced respiration compared with 21{\%} O2-maintained cells. Western blot analysis showed an increase in the association of Hsp90-eNOS and enhanced NO generation on hypoxia exposure, whereas there was no significant accumulation of hypoxia-inducible factor-1α (HIF-1α). The addition of inhibitors of Hsp90, phosphatidylinositol 3-kinase, and NOS significantly alleviated this hypoxia-induced attenuation of respiration. Thus we conclude that hypoxia-induced excess NO and its derivatives such as ONOO- cause inhibition of the electron transport chain and attenuate O2 demand, leading to cell survival at extreme hypoxia. More importantly, such an attenuation is found to be independent of HIF-1α, which is otherwise thought to be the key regulator of respiration in hypoxia-exposed cells, through a nonphosphorylative glycolytic pathway. The present mechanistic insight will be helpful to understand the difference in the magnitude of endothelial dysfunction.",
keywords = "Electron paramagnetic resonance oximetry, Endothelial nitric oxide synthase, Heat shock protein 90, Oxygen",
author = "Tennille Presley and Kaushik Vedam and Murugesan Velayutham and Zweier, {Jay L.} and Govindasamy Ilangovan",
year = "2008",
month = "11",
doi = "10.1152/ajpcell.00550.2007",
language = "English (US)",
volume = "295",
journal = "American Journal of Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "5",

}

TY - JOUR

T1 - Activation of Hsp90-eNOS and increased NO generation attenuate respiration of hypoxia-treated endothelial cells

AU - Presley, Tennille

AU - Vedam, Kaushik

AU - Velayutham, Murugesan

AU - Zweier, Jay L.

AU - Ilangovan, Govindasamy

PY - 2008/11

Y1 - 2008/11

N2 - Hypoxia induces various adoptive signaling in cells that can cause several physiological changes. In the present work, we have observed that exposure of bovine aortic endothelial cells (BAECs) to extreme hypoxia (1-5% O2) attenuates cellular respiration by a mechanism involving heat shock protein 90 (Hsp90) and endothelial nitric oxide (NO) synthase (eNOS), so that the cells are conditioned to consume less oxygen and survive in prolonged hypoxic conditions. BAECs, exposed to 1% O2, showed a reduced respiration compared with 21% O2-maintained cells. Western blot analysis showed an increase in the association of Hsp90-eNOS and enhanced NO generation on hypoxia exposure, whereas there was no significant accumulation of hypoxia-inducible factor-1α (HIF-1α). The addition of inhibitors of Hsp90, phosphatidylinositol 3-kinase, and NOS significantly alleviated this hypoxia-induced attenuation of respiration. Thus we conclude that hypoxia-induced excess NO and its derivatives such as ONOO- cause inhibition of the electron transport chain and attenuate O2 demand, leading to cell survival at extreme hypoxia. More importantly, such an attenuation is found to be independent of HIF-1α, which is otherwise thought to be the key regulator of respiration in hypoxia-exposed cells, through a nonphosphorylative glycolytic pathway. The present mechanistic insight will be helpful to understand the difference in the magnitude of endothelial dysfunction.

AB - Hypoxia induces various adoptive signaling in cells that can cause several physiological changes. In the present work, we have observed that exposure of bovine aortic endothelial cells (BAECs) to extreme hypoxia (1-5% O2) attenuates cellular respiration by a mechanism involving heat shock protein 90 (Hsp90) and endothelial nitric oxide (NO) synthase (eNOS), so that the cells are conditioned to consume less oxygen and survive in prolonged hypoxic conditions. BAECs, exposed to 1% O2, showed a reduced respiration compared with 21% O2-maintained cells. Western blot analysis showed an increase in the association of Hsp90-eNOS and enhanced NO generation on hypoxia exposure, whereas there was no significant accumulation of hypoxia-inducible factor-1α (HIF-1α). The addition of inhibitors of Hsp90, phosphatidylinositol 3-kinase, and NOS significantly alleviated this hypoxia-induced attenuation of respiration. Thus we conclude that hypoxia-induced excess NO and its derivatives such as ONOO- cause inhibition of the electron transport chain and attenuate O2 demand, leading to cell survival at extreme hypoxia. More importantly, such an attenuation is found to be independent of HIF-1α, which is otherwise thought to be the key regulator of respiration in hypoxia-exposed cells, through a nonphosphorylative glycolytic pathway. The present mechanistic insight will be helpful to understand the difference in the magnitude of endothelial dysfunction.

KW - Electron paramagnetic resonance oximetry

KW - Endothelial nitric oxide synthase

KW - Heat shock protein 90

KW - Oxygen

UR - http://www.scopus.com/inward/record.url?scp=57349158553&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=57349158553&partnerID=8YFLogxK

U2 - 10.1152/ajpcell.00550.2007

DO - 10.1152/ajpcell.00550.2007

M3 - Article

C2 - 18787079

AN - SCOPUS:57349158553

VL - 295

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6135

IS - 5

ER -