NADPH oxidases in heart failure: poachers or gamekeepers?
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Journal: 2013/August - Antioxidants and Redox Signaling
ISSN: 1557-7716
Abstract:
CONCLUSIONS
Oxidative stress is involved in the pathogenesis of heart failure but clinical antioxidant trials have been unsuccessful. This may be because effects of reactive oxygen species (ROS) depend upon their source, location, and concentration. Nicotinamide adenine dinucleotide phosphate oxidase (Nox) proteins generate ROS in a highly regulated fashion and modulate several components of the heart failure phenotype.
BACKGROUND
Two Nox isoforms, Nox2 and Nox4, are expressed in the heart. Studies using gene-modified mice deficient in Nox2 activity indicate that Nox2 activation contributes to angiotensin II-induced cardiomyocyte hypertrophy, atrial fibrillation, and the development of interstitial fibrosis but may also positively modulate physiological excitation-contraction coupling. Nox2 contributes to myocyte death under stress situations and plays important roles in postmyocardial infarction remodeling, in part by modulating matrix metalloprotease activity. In contrast to Nox2, Nox4 is constitutively active at a low level and induces protective effects in the heart under chronic stress, for example, by maintaining myocardial capillary density. However, high levels of Nox4 could have detrimental effects.
RESULTS
The effects of Nox proteins during the development of heart failure likely depend upon the isoform, activation level, and cellular distribution, and may include beneficial as well as detrimental effects. More needs to be learnt about the precise regulation of abundance and biochemical activity of these proteins in the heart as well as the downstream signaling pathways that they regulate.
CONCLUSIONS
The development of specific approaches to target individual Nox isoforms and/or specific cell types may be important for the achievement of therapeutic efficacy in heart failure.
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Antioxid Redox Signal 18(9): 1024-1041
PMID: 22747566

NADPH Oxidases in Heart Failure: Poachers or Gamekeepers?

Cardiovascular Division, James Black Centre, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
Department of Genetics, Biology and Biochemistry, Molecular Biotechnology Center, University of Torino, Torino, Italy.
Corresponding author.
Address correspondence to: Prof. Ajay M. Shah, Cardiovascular Division, James Black Centre, King's College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, London SE5 9NU, United Kingdom. E-mail:ku.ca.lck@hahs.yaja
Address correspondence to: Prof. Ajay M. Shah, Cardiovascular Division, James Black Centre, King's College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, London SE5 9NU, United Kingdom. E-mail:ku.ca.lck@hahs.yaja
Received 2012 Jan 30; Revised 2012 Jun 15; Accepted 2012 Jul 1.
Copyright 2013, Mary Ann Liebert, Inc.

Abstract

Significance: Oxidative stress is involved in the pathogenesis of heart failure but clinical antioxidant trials have been unsuccessful. This may be because effects of reactive oxygen species (ROS) depend upon their source, location, and concentration. Nicotinamide adenine dinucleotide phosphate oxidase (Nox) proteins generate ROS in a highly regulated fashion and modulate several components of the heart failure phenotype. Recent Advances: Two Nox isoforms, Nox2 and Nox4, are expressed in the heart. Studies using gene-modified mice deficient in Nox2 activity indicate that Nox2 activation contributes to angiotensin II–induced cardiomyocyte hypertrophy, atrial fibrillation, and the development of interstitial fibrosis but may also positively modulate physiological excitation-contraction coupling. Nox2 contributes to myocyte death under stress situations and plays important roles in postmyocardial infarction remodeling, in part by modulating matrix metalloprotease activity. In contrast to Nox2, Nox4 is constitutively active at a low level and induces protective effects in the heart under chronic stress, for example, by maintaining myocardial capillary density. However, high levels of Nox4 could have detrimental effects. Critical Issues: The effects of Nox proteins during the development of heart failure likely depend upon the isoform, activation level, and cellular distribution, and may include beneficial as well as detrimental effects. More needs to be learnt about the precise regulation of abundance and biochemical activity of these proteins in the heart as well as the downstream signaling pathways that they regulate. Future Directions: The development of specific approaches to target individual Nox isoforms and/or specific cell types may be important for the achievement of therapeutic efficacy in heart failure. Antioxid. Redox Signal. 18, 1024–1041.

Abstract

Abbreviations Used

AFatrial fibrillation
Aldoaldosterone
ANFatrial natriuretic factor
AngIIangiotensin II
ARadrenoreceptor
ASK-1apoptosis signal-regulating kinase 1
CaMKIICa(2+)/calmodulin-dependent protein kinase II
CHFchronic heart failure
CTGFconnective tissue growth factor
Duoxdual oxidase
Duoxaduox activator
ECCexcitation-contraction coupling
ECsendothelial cells
ERendoplasmic reticulum
Erkextracellular signal-regulated kinase
GEFsguanine-nucleotide-exchange factors
GPCRsG-protein coupled receptor agonists
H2O2hydrogen peroxide
HIF1αhypoxia-inducible factor-1α
HRPhorseradish peroxidase
LCCL-type calcium channels
LVHleft ventricular hypertrophy
MAPKmitogen-activated protein kinase
MEF2myocyte enhancer factors 2
MImyocardial infarction
MMPsmatrix metalloproteinases
MPOsmyeloperoxidases
MsrAmethionine sulfoxide reductase A
NADPHnicotinamide adenine dinucleotide phosphate
NCXsodium-calcium exchange
NF-κBnuclear factor kappa-light-chain-enhancer of activated B cells
NOnitric oxide
NOSsnitric oxide synthases
NoxNADPH oxidase
Noxa1Nox activator 1
Noxo1Nox organizer 1
NRVMneonatal rat ventricular myocytes
ONOO−peroxynitrite
ox-LDLoxidized low-density lipoprotein
PDGFplatelet-derived growth factor
PHDprolyl hydroxylases
phoxphagocytic oxidase
PI3Kphosphoinositide-3-kinase
PIP3phosphatidylinositol(3, 4, 5)trisphosphate
PKCprotein kinase C
PKDprotein kinase D
PLA2phospholipase A2
PLDphospholipase D
ROSreactive oxygen species
RTKreceptor tyrosine kinase
RyRryanodine receptor
SERCASR calcium ATPase pump
SH3Src homology 3
SODsuperoxide dismutase
SRsarcoplasmic reticulum
TNF-αtumor necrosis factor-α
T-TT tubule
VSMCsvascular smooth muscle cells
WISP1WNT1 inducible signaling pathway protein 1
XOsxanthine oxidases
Abbreviations Used

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