AMP-activated protein kinase and hypoxic pulmonary vasoconstriction

TY - JOUR

T1 - AMP-activated protein kinase and hypoxic pulmonary vasoconstriction

A1 - Robertson,Tom P.

A1 - Mustard,Kirsteen J. W.

A1 - Lewis,Tristan H.

A1 - Clark,Jill H.

A1 - Wyatt,Christopher N.

A1 - Blanco,Elisa A.

A1 - Peers,Chris

A1 - Hardie,D. Grahame

A1 - Evans,A. Mark

AU - Robertson,Tom P.

AU - Mustard,Kirsteen J. W.

AU - Lewis,Tristan H.

AU - Clark,Jill H.

AU - Wyatt,Christopher N.

AU - Blanco,Elisa A.

AU - Peers,Chris

AU - Hardie,D. Grahame

AU - Evans,A. Mark

PY - 2008/10/24

Y1 - 2008/10/24

N2 - <p>Hypoxic pulmonary vasoconstriction is a vital homeostatic mechanism that aids ventilation-perfusion matching in the lung, for which the underlying mechanism(s) remains controversial. However, our most recent investigations strongly suggest that hypoxic pulmonary vasoconstriction is precipitated, at least in part, by the inhibition of mitochondrial oxidative phosphorylation by hypoxia, an increase in the AMP/ATP ratio and consequent activation of AMP-activated protein kinase (AMPK). Unfortunately, these studies lacked the definitive proof that can only be provided by selectively blocking AMPK-dependent signalling cascades. The aim of the present study was. therefore, to determine the effects of the AMPK inhibitor compound C upon: (1) phosphorylation in response to hypoxia of a classical AMPK substrate, acetyl CoA carboxylase, in rat pulmonary arterial smooth muscle and (2) hypoxic pulmonary vasoconstriction in isolated intrapulmonary arteries. Acetyl CoA carboxylase phosphorylation was increased approximately 3 fold in the presence of hypoxia (pO(2) = 16-21 mm Hg, 1 h) and 5-aminoimidazole-4-carboxamide riboside (AICAR; 1 mM; 4 h) and in a manner that was significantly attenuated by the AMPK antagonist compound C (40 mu M). Most importantly, pre-incubation of intrapulmonary arteries with compound C (40 mu M) inhibited phase II, but not phase I, of hypoxic pulmonary vasoconstriction. Likewise, compound C (40 mu M) inhibited constriction by AICAR (1 mM). The results of the present study are consistent with the activation of AMPK being a key event in the initiation of the contractile response of pulmonary arteries to acute hypoxia. (C) 2008 Elsevier B.V. All rights reserved.</p>

AB - <p>Hypoxic pulmonary vasoconstriction is a vital homeostatic mechanism that aids ventilation-perfusion matching in the lung, for which the underlying mechanism(s) remains controversial. However, our most recent investigations strongly suggest that hypoxic pulmonary vasoconstriction is precipitated, at least in part, by the inhibition of mitochondrial oxidative phosphorylation by hypoxia, an increase in the AMP/ATP ratio and consequent activation of AMP-activated protein kinase (AMPK). Unfortunately, these studies lacked the definitive proof that can only be provided by selectively blocking AMPK-dependent signalling cascades. The aim of the present study was. therefore, to determine the effects of the AMPK inhibitor compound C upon: (1) phosphorylation in response to hypoxia of a classical AMPK substrate, acetyl CoA carboxylase, in rat pulmonary arterial smooth muscle and (2) hypoxic pulmonary vasoconstriction in isolated intrapulmonary arteries. Acetyl CoA carboxylase phosphorylation was increased approximately 3 fold in the presence of hypoxia (pO(2) = 16-21 mm Hg, 1 h) and 5-aminoimidazole-4-carboxamide riboside (AICAR; 1 mM; 4 h) and in a manner that was significantly attenuated by the AMPK antagonist compound C (40 mu M). Most importantly, pre-incubation of intrapulmonary arteries with compound C (40 mu M) inhibited phase II, but not phase I, of hypoxic pulmonary vasoconstriction. Likewise, compound C (40 mu M) inhibited constriction by AICAR (1 mM). The results of the present study are consistent with the activation of AMPK being a key event in the initiation of the contractile response of pulmonary arteries to acute hypoxia. (C) 2008 Elsevier B.V. All rights reserved.</p>

KW - AMP-activated protein kinase

KW - hypoxic pulmonary vasoconstriction

KW - compound C

KW - AICAR

KW - MITOCHONDRIAL OXIDATIVE-PHOSPHORYLATION

KW - COUPLE INHIBITION

KW - O-2-SENSING CELLS

KW - RAT LUNG

KW - LKB1

KW - METFORMIN

KW - CALCIUM

KW - MUSCLE

KW - ARTERY

KW - CHEMORECEPTORS

U2 - 10.1016/j.ejphar.2008.07.035

DO - 10.1016/j.ejphar.2008.07.035

M1 - Article

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 1-3

VL - 595

SP - 39

EP - 43

ER -