NADPH oxidases in vascular pathology.
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Journal: 2014/December - Antioxidants and Redox Signaling
ISSN: 1557-7716
Abstract:
CONCLUSIONS
Reactive oxygen species (ROS) play a critical role in vascular disease. While there are many possible sources of ROS, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases play a central role. They are a source of "kindling radicals," which affect other enzymes, such as nitric oxide synthase endothelial nitric oxide synthase or xanthine oxidase. This is important, as risk factors for atherosclerosis (hypertension, diabetes, hypercholesterolemia, and smoking) regulate the expression and activity of NADPH oxidases in the vessel wall.
BACKGROUND
There are seven isoforms in mammals: Nox1, Nox2, Nox3, Nox4, Nox5, Duox1 and Duox2. Nox1, Nox2, Nox4, and Nox5 are expressed in endothelium, vascular smooth muscle cells, fibroblasts, or perivascular adipocytes. Other homologues have not been found or are expressed at very low levels; their roles have not been established. Nox1/Nox2 promote the development of endothelial dysfunction, hypertension, and inflammation. Nox4 may have a role in protecting the vasculature during stress; however, when its activity is increased, it may be detrimental. Calcium-dependent Nox5 has been implicated in oxidative damage in human atherosclerosis.
RESULTS
NADPH oxidase-derived ROS play a role in vascular pathology as well as in the maintenance of normal physiological vascular function. We also discuss recently elucidated mechanisms such as the role of NADPH oxidases in vascular protection, vascular inflammation, pulmonary hypertension, tumor angiogenesis, and central nervous system regulation of vascular function and hypertension.
CONCLUSIONS
Understanding the role of individual oxidases and interactions between homologues in vascular disease is critical for efficient pharmacological regulation of vascular NADPH oxidases in both the laboratory and clinical practice.
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Antioxid Redox Signal 20(17): 2794-2814
PMID: 24180474

NADPH Oxidases in Vascular Pathology

Department of Internal Medicine, Jagiellonian University School of Medicine, Cracow, Poland.
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
Corresponding author.
Address correspondence to:, Prof. Tomasz J. Guzik, Translational Medicine Laboratory, Department of Internal and Agricultural Medicine, Jagiellonian University School of Medicine, J Dietl Hospital, Ul. Skarbowa 1, 31-121 Cracow, Poland,
E-mail:moc.em@kizugt
Address correspondence to:, Prof. Tomasz J. Guzik, Translational Medicine Laboratory, Department of Internal and Agricultural Medicine, Jagiellonian University School of Medicine, J Dietl Hospital, Ul. Skarbowa 1, 31-121 Cracow, Poland,
E-mail:moc.em@kizugt
Received 2013 Aug 28; Accepted 2013 Sep 7.
Copyright 2014, Mary Ann Liebert, Inc.

Abstract

Significance: Reactive oxygen species (ROS) play a critical role in vascular disease. While there are many possible sources of ROS, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases play a central role. They are a source of “kindling radicals,” which affect other enzymes, such as nitric oxide synthase endothelial nitric oxide synthase or xanthine oxidase. This is important, as risk factors for atherosclerosis (hypertension, diabetes, hypercholesterolemia, and smoking) regulate the expression and activity of NADPH oxidases in the vessel wall. Recent Advances: There are seven isoforms in mammals: Nox1, Nox2, Nox3, Nox4, Nox5, Duox1 and Duox2. Nox1, Nox2, Nox4, and Nox5 are expressed in endothelium, vascular smooth muscle cells, fibroblasts, or perivascular adipocytes. Other homologues have not been found or are expressed at very low levels; their roles have not been established. Nox1/Nox2 promote the development of endothelial dysfunction, hypertension, and inflammation. Nox4 may have a role in protecting the vasculature during stress; however, when its activity is increased, it may be detrimental. Calcium-dependent Nox5 has been implicated in oxidative damage in human atherosclerosis. Critical Issues: NADPH oxidase-derived ROS play a role in vascular pathology as well as in the maintenance of normal physiological vascular function. We also discuss recently elucidated mechanisms such as the role of NADPH oxidases in vascular protection, vascular inflammation, pulmonary hypertension, tumor angiogenesis, and central nervous system regulation of vascular function and hypertension. Future Directions: Understanding the role of individual oxidases and interactions between homologues in vascular disease is critical for efficient pharmacological regulation of vascular NADPH oxidases in both the laboratory and clinical practice. Antioxid. Redox Signal. 20, 2794–2814.

Abstract

Abbreviations Used

17DMAG17-dimethylaminoethylamino-17-demethoxygeldanamycin
AAAabdominal aortic aneurysm
AEBSF4-(2-aminoethyl)-benzenesulfonylfluoride
Ang IIangiotensin II
ApoEapolipoprotein E
AT1angiotensin receptor type 1
BH4tetrahydrobiopterin
Ca2+calcium
CCL2chemokine (C-C motif) ligand 2
CGDchronic granulomatous disease
CVOscircumventricular organs
DGLAdihomo-gamma-linolenic acid
DPIdiphenylene iodonium
Duox1dual oxidase1
EGFepidermal growth factor
eNOSendothelial nitric oxide synthase
ERendoplasmic reticulum
ET-1endothelin 1
H2O2hydrogen peroxide
HIF-1αhypoxia-inducible factor-1α
HO-1heme oxygenase-1
HUVECshuman umbilical vein endothelial cells
ICAM-1intercellular adhesion molecule 1
IL-6interleukin 6
KOXkidney oxidase
LDLlow density lipoprotein
MAP kinasemitogen activated protein kinase
MCP-1monocyte chemoattractant protein-1
MHCmajor histocompatibility complex
MMP-2matrix metalloproteinase 2
MMP-9matrix metalloproteinase 9
MPOmyeloperoxidase
NACN-acetylcysteine
NADPHnicotinamide adenine dinucleotide phosphate
NF-κBnuclear factor kappa-light-chain-enhancer of activated B cells
NOnitric oxide
NoXA1Nox activator protein 1
NoXO1Nox organizer protein 1
O2−superoxide anion
PASMCspulmonary artery smooth muscle cells
PDGFplatelet-derived growth factor
PKCprotein kinase C
PLA2phospholipase A2
PPARγperoxisome proliferator-activated receptor gamma
RANTESregulated on activation, normal T cell expressed and secreted
ROSreactive oxygen species
RVLMrostral ventrolateral medulla
{"type":"entrez-protein","attrs":{"text":"S17834","term_id":"93707","term_text":"pir||S17834"}}S178346,8-diallyl 5,7-dihydroxy 2-(2-allyl 3-hydroxy 4-methoxyphenyl)1-H benzo(b)pyran-4-one
SFOsubfornical organ
SHRspontaneously hypertensive rat
SMCsmooth muscle cell
SOD3superoxide dismutase 3
STZstreptozotocin
TGF-αtransforming growth factor α
TGF-βtransforming growth factor β
TNF-αtumor necrosis factor-α
VCAM-1vascular cell adhesion molecule 1
VEGFvascular endothelial growth factor
VSMCvascular smooth muscle cell
XJP-17,8-Dihydroxy-3-methyl-isochromanone-4
Abbreviations Used

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