Inhibition of the pentose phosphate pathway decreases ischemia-reperfusion-induced creatine kinase release in the heart

C. J. Zuurbier; P. T. Goedhart; E. A. Struys; N. M. Verhoeven; C. Jakobs; C. Ince

doi:https://doi.org/10.1016/j.cardiores.2004.01.010

Inhibition of the pentose phosphate pathway decreases ischemia-reperfusion-induced creatine kinase release in the heart

C. J. Zuurbier, P. T. Goedhart, E. A. Struys, N. M. Verhoeven, C. Jakobs, C. Ince

Research output: Contribution to journal › Article › Academic › peer-review

47 Citations (Scopus)

Abstract

Objective: The oxidative pentose phosphate pathway (oxPPP) produces NADPH, which can be used to maintain glutathione in its reduced state (anti-oxidant; beneficial effects) or to produce radicals or nitric oxide (NO) through NADPH oxidase/NO synthase (detrimental effects). Changes in cytosolic redox status have been implicated in ischemic preconditioning (PC). This study investigates whether (1) PC affects mitochondrial redox state, (2) the oxPPP plays a protective or detrimental role in ischemia (I)-reperfusion (R) injury in the intact heart and (3) PPP is altered with PC. Methods: Isolated rat hearts were subjected to 40-min global I and 30-min R (CO, control). Ischemia was either preceded by three 5-min I/R periods (PC) and/or oxPPP inhibition by 6-aminonicotinamide (6AN) or NADPH oxidase/NO synthase inhibition by diphenyleneiodonium (DPI). NADH videofluorometry was used to determine mitochondrial redox state. PPP intermediates were determined in CO and PC hearts using tandem mass spectrometry. Results: PC reduced ischemic damage (creatine kinase, CK, release from 337 +/- 64 to 147 +/- 41 U/R/g(dw)) and contracture (from 59 +/- 5 to 31 +/- 3 mm Hg) and increased recovery of contractility (from 48 +/- 10% to 88 +/- 8%), as compared to CO. PC was without effect on NADH fluorometry. Inhibition of the oxPPP reduced injury (CK release: 91 +/- 24 U/R/g(dw)) to similar levels as PC,. without improving contractility. Inhibition of NADPH oxidase/NO synthase mimicked the effects of oxPPP inhibition on injury (CK release: 140 +/- 22 U/R/g(dw)). Although levels of ribose-5P and (ribulose-5P + xylulose-5P) rose several fold during ischemia with minor changes in sedoheptulose-7P, demonstrating an active PPP in the heart, PC did not affect these levels. Conclusions: (1) PC can attenuate cardiac reperfusion injury without alterations in mitochondrial redox state; (2) inhibition of the oxPPP protects the heart against I/R-induced CK release; and (3) PC does not result in altered activity of the PPP. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved

Original language	English
Pages (from-to)	145-153
Journal	Cardiovascular research
Volume	62
Issue number	1
DOIs	https://doi.org/10.1016/j.cardiores.2004.01.010
Publication status	Published - 2004

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https://doi.org/10.1016/j.cardiores.2004.01.010

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@article{3d38e069a9dc494cb25b560830c7d3e4,

title = "Inhibition of the pentose phosphate pathway decreases ischemia-reperfusion-induced creatine kinase release in the heart",

abstract = "Objective: The oxidative pentose phosphate pathway (oxPPP) produces NADPH, which can be used to maintain glutathione in its reduced state (anti-oxidant; beneficial effects) or to produce radicals or nitric oxide (NO) through NADPH oxidase/NO synthase (detrimental effects). Changes in cytosolic redox status have been implicated in ischemic preconditioning (PC). This study investigates whether (1) PC affects mitochondrial redox state, (2) the oxPPP plays a protective or detrimental role in ischemia (I)-reperfusion (R) injury in the intact heart and (3) PPP is altered with PC. Methods: Isolated rat hearts were subjected to 40-min global I and 30-min R (CO, control). Ischemia was either preceded by three 5-min I/R periods (PC) and/or oxPPP inhibition by 6-aminonicotinamide (6AN) or NADPH oxidase/NO synthase inhibition by diphenyleneiodonium (DPI). NADH videofluorometry was used to determine mitochondrial redox state. PPP intermediates were determined in CO and PC hearts using tandem mass spectrometry. Results: PC reduced ischemic damage (creatine kinase, CK, release from 337 +/- 64 to 147 +/- 41 U/R/g(dw)) and contracture (from 59 +/- 5 to 31 +/- 3 mm Hg) and increased recovery of contractility (from 48 +/- 10% to 88 +/- 8%), as compared to CO. PC was without effect on NADH fluorometry. Inhibition of the oxPPP reduced injury (CK release: 91 +/- 24 U/R/g(dw)) to similar levels as PC,. without improving contractility. Inhibition of NADPH oxidase/NO synthase mimicked the effects of oxPPP inhibition on injury (CK release: 140 +/- 22 U/R/g(dw)). Although levels of ribose-5P and (ribulose-5P + xylulose-5P) rose several fold during ischemia with minor changes in sedoheptulose-7P, demonstrating an active PPP in the heart, PC did not affect these levels. Conclusions: (1) PC can attenuate cardiac reperfusion injury without alterations in mitochondrial redox state; (2) inhibition of the oxPPP protects the heart against I/R-induced CK release; and (3) PC does not result in altered activity of the PPP. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved",

author = "Zuurbier, {C. J.} and Goedhart, {P. T.} and Struys, {E. A.} and Verhoeven, {N. M.} and C. Jakobs and C. Ince",

year = "2004",

doi = "https://doi.org/10.1016/j.cardiores.2004.01.010",

language = "English",

volume = "62",

pages = "145--153",

journal = "Cardiovascular research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "1",

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TY - JOUR

T1 - Inhibition of the pentose phosphate pathway decreases ischemia-reperfusion-induced creatine kinase release in the heart

AU - Zuurbier, C. J.

AU - Goedhart, P. T.

AU - Struys, E. A.

AU - Verhoeven, N. M.

AU - Jakobs, C.

AU - Ince, C.

PY - 2004

Y1 - 2004

N2 - Objective: The oxidative pentose phosphate pathway (oxPPP) produces NADPH, which can be used to maintain glutathione in its reduced state (anti-oxidant; beneficial effects) or to produce radicals or nitric oxide (NO) through NADPH oxidase/NO synthase (detrimental effects). Changes in cytosolic redox status have been implicated in ischemic preconditioning (PC). This study investigates whether (1) PC affects mitochondrial redox state, (2) the oxPPP plays a protective or detrimental role in ischemia (I)-reperfusion (R) injury in the intact heart and (3) PPP is altered with PC. Methods: Isolated rat hearts were subjected to 40-min global I and 30-min R (CO, control). Ischemia was either preceded by three 5-min I/R periods (PC) and/or oxPPP inhibition by 6-aminonicotinamide (6AN) or NADPH oxidase/NO synthase inhibition by diphenyleneiodonium (DPI). NADH videofluorometry was used to determine mitochondrial redox state. PPP intermediates were determined in CO and PC hearts using tandem mass spectrometry. Results: PC reduced ischemic damage (creatine kinase, CK, release from 337 +/- 64 to 147 +/- 41 U/R/g(dw)) and contracture (from 59 +/- 5 to 31 +/- 3 mm Hg) and increased recovery of contractility (from 48 +/- 10% to 88 +/- 8%), as compared to CO. PC was without effect on NADH fluorometry. Inhibition of the oxPPP reduced injury (CK release: 91 +/- 24 U/R/g(dw)) to similar levels as PC,. without improving contractility. Inhibition of NADPH oxidase/NO synthase mimicked the effects of oxPPP inhibition on injury (CK release: 140 +/- 22 U/R/g(dw)). Although levels of ribose-5P and (ribulose-5P + xylulose-5P) rose several fold during ischemia with minor changes in sedoheptulose-7P, demonstrating an active PPP in the heart, PC did not affect these levels. Conclusions: (1) PC can attenuate cardiac reperfusion injury without alterations in mitochondrial redox state; (2) inhibition of the oxPPP protects the heart against I/R-induced CK release; and (3) PC does not result in altered activity of the PPP. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved

AB - Objective: The oxidative pentose phosphate pathway (oxPPP) produces NADPH, which can be used to maintain glutathione in its reduced state (anti-oxidant; beneficial effects) or to produce radicals or nitric oxide (NO) through NADPH oxidase/NO synthase (detrimental effects). Changes in cytosolic redox status have been implicated in ischemic preconditioning (PC). This study investigates whether (1) PC affects mitochondrial redox state, (2) the oxPPP plays a protective or detrimental role in ischemia (I)-reperfusion (R) injury in the intact heart and (3) PPP is altered with PC. Methods: Isolated rat hearts were subjected to 40-min global I and 30-min R (CO, control). Ischemia was either preceded by three 5-min I/R periods (PC) and/or oxPPP inhibition by 6-aminonicotinamide (6AN) or NADPH oxidase/NO synthase inhibition by diphenyleneiodonium (DPI). NADH videofluorometry was used to determine mitochondrial redox state. PPP intermediates were determined in CO and PC hearts using tandem mass spectrometry. Results: PC reduced ischemic damage (creatine kinase, CK, release from 337 +/- 64 to 147 +/- 41 U/R/g(dw)) and contracture (from 59 +/- 5 to 31 +/- 3 mm Hg) and increased recovery of contractility (from 48 +/- 10% to 88 +/- 8%), as compared to CO. PC was without effect on NADH fluorometry. Inhibition of the oxPPP reduced injury (CK release: 91 +/- 24 U/R/g(dw)) to similar levels as PC,. without improving contractility. Inhibition of NADPH oxidase/NO synthase mimicked the effects of oxPPP inhibition on injury (CK release: 140 +/- 22 U/R/g(dw)). Although levels of ribose-5P and (ribulose-5P + xylulose-5P) rose several fold during ischemia with minor changes in sedoheptulose-7P, demonstrating an active PPP in the heart, PC did not affect these levels. Conclusions: (1) PC can attenuate cardiac reperfusion injury without alterations in mitochondrial redox state; (2) inhibition of the oxPPP protects the heart against I/R-induced CK release; and (3) PC does not result in altered activity of the PPP. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved

U2 - https://doi.org/10.1016/j.cardiores.2004.01.010

DO - https://doi.org/10.1016/j.cardiores.2004.01.010

M3 - Article

C2 - 15023561

SN - 0008-6363

VL - 62

SP - 145

EP - 153

JO - Cardiovascular research

JF - Cardiovascular research

IS - 1

ER -