A Possible Target of Antioxidative Therapy for Diabetic Vascular Complications-Vascular NAD(P)H Oxidase

Inoguchi, Toyoshi; Tsubouchi, Hirohito; Etoh, Takashi; Kakimoto, Maiko; Sonta, Toshiyo; Utsumi, Hideo; Sumimoto, Hideki; Hai, Yu; Sonoda, Noriyuki; Inuo, M.; Sato, Nobuyoshi; Sekiguchi, Naotaka; Kobayashi, Kazuo; Nawata, Hajime

doi:10.2174/0929867033457133

Cited by 45 publications

(30 citation statements)

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“…Diabetes and high glucose conditions can increase the formation of ROS by multiple biochemical pathways, including glucose auto-oxidation, activation of the polyol pathway which can decrease levels of reduced glutathione and/or increase advanced glycation end products and activation of PKC which activates NAD(P)H oxidase (Fig. 10) (Brownlee, 2001;Brownlee, 2005;Inoguchi et al, 2003a;Inoguchi et al, 2003b;Jain, 2006). All of these events have been suggested to be initiated by superoxide overproduction by the mitochondrial electron-transport chain (Brownlee, 2005).…”

Section: Oxidative Stress and Diabetic Retinopathymentioning

confidence: 99%

“…However, while mitochondrial-derived ROS are important for the initiation of oxidative stress responses in models of hyperglycemia, studies in other models indicate that activity of NADPH oxidase is required in order to sustain sufficient levels of ROS formation for the transduction of specific cellular responses (Kimura et al, 2005;Lee et al, 2006b;Schafer et al, 2003). Data showing increased activity of NAD(P)H oxidase in retinas and vascular tissues of diabetic patients and animals and in high glucose-treated endothelial cells suggest that NAD(P)H oxidase is an important source of ROS in the diabetic milieu (Al-Shabrawey et al, In Pressa; Al-Shabrawey et al, In Press-b; Al-Shabrawey et al, 2006;Ellis et al, 1998;Griendling et al, 2000;Inoguchi et al, 2003b;Sonta et al, 2004). Studies using a mouse model for ischemic retinopathy have revealed that superoxide production by NAD(P)H oxidase has a primary role in VEGF expression and retinal neovascularization (Al-Shabrawey et al, 2005).…”

Section: Oxidative Stress and Diabetic Retinopathymentioning

confidence: 99%

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Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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Section: Oxidative Stress and Diabetic Retinopathymentioning

confidence: 99%

Section: Oxidative Stress and Diabetic Retinopathymentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

View full text Add to dashboard Cite

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“…The source of ROS generated during lipotoxicity is controversial. Recent evidence, from a variety of cell types, suggests that processes other than mitochondrial ␤-oxidation, such as NADPH oxidase activity, may be involved (Inoguchi et al, 2003;Quagliaro et al, 2003;Cacicedo et al, 2005).Because oxidative stress is closely linked to ER stress (Oyadomari and Mori, 2004), we hypothesized that eEF1A-1 mediates lipotoxic cell death in response ROS-induced ER stress in cardiomyocytes. Oxidative stress-induced apoptosis requires the release of ER calcium ions (Scorrano et al, 2003), and depletion of these stores can impair normal protein-folding functions, leading to ER stress (Rao et al, 2004;Rutkowski and Kaufman, 2004).…”

mentioning

confidence: 97%

A Critical Role for Eukaryotic Elongation Factor 1A-1 in Lipotoxic Cell Death

Borradaile

Buhman

Listenberger

et al. 2006

MBoC

138

163

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The deleterious consequences of fatty acid (FA) and neutral lipid accumulation in nonadipose tissues, such as the heart, contribute to the pathogenesis of type 2 diabetes. To elucidate mechanisms of FA-induced cell death, or lipotoxicity, we generated Chinese hamster ovary (CHO) cell mutants resistant to palmitate-induced death and isolated a clone with disruption of eukaryotic elongation factor (eEF) 1A-1. eEF1A-1 involvement in lipotoxicity was confirmed in H9c2 cardiomyoblasts, in which small interfering RNA-mediated knockdown also conferred palmitate resistance. In wild-type CHO and H9c2 cells, palmitate increased reactive oxygen species and induced endoplasmic reticulum (ER) stress, changes accompanied by increased eEF1A-1 expression. Disruption of eEF1A-1 expression rendered these cells resistant to hydrogen peroxide-and ER stress-induced death, indicating that eEF1A-1 plays a critical role in the cell death response to these stressors downstream of lipid overload. Disruption of eEF1A-1 also resulted in actin cytoskeleton defects under basal conditions and in response to palmitate, suggesting that eEF1A-1 mediates lipotoxic cell death, secondary to oxidative and ER stress, by regulating cytoskeletal changes critical for this process. Furthermore, our observations of oxidative stress, ER stress, and induction of eEF1A-1 expression in a mouse model of lipotoxic cardiomyopathy implicate this cellular response in the pathophysiology of metabolic disease. INTRODUCTIONThe increased prevalence of obesity worldwide has contributed to the emergence of a disease cluster, the metabolic syndrome, that includes insulin resistance, type 2 diabetes, and cardiovascular disease. Elevated serum triglyceride and fatty acid (FA) levels associated with this syndrome contribute to lipid accumulation in many nonadipose tissues, including the heart. This inappropriate accumulation of excess lipid can lead to cellular dysfunction and cell death-a process called lipotoxicity (Unger, 2003).Lipotoxic cardiomyocyte death has been proposed to play a central role in heart failure associated with diabetes and obesity in animal models and in humans. Although FAs are the principal source of energy for cardiomyocytes, high serum triglyceride and FA levels result in FA uptake by the heart that exceeds the anabolic and catabolic needs of the tissue. Triglyceride accumulation in cardiomyocytes of leptin-or leptin receptor-deficient obese diabetic animal models is associated with cardiomyocyte apoptosis (Zhou et al., 2000) and contractile dysfunction (Zhou et al., 2000;Aasum et al., 2002;Christoffersen et al., 2003), suggesting that lipotoxic cell death in the heart may be important in the genesis of diabetic cardiomyopathy. Recently, similar observations were reported in patients with metabolic syndrome and nonischemic heart failure (Sharma et al., 2004). Consistent with this apparent cardiac lipotoxicity, cardiomyocyte-specific increases in FA uptake in mice with cardiac-restricted overexpression of long-chain acyl-CoA synthetase 1 (ACS1), li...

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“…In many types of cells, including TAL cells, activation of protein kinase C (PKC) has been shown to stimulate O 2 . production in response to different stimuli, including Ang II (23,24,25). The PKC family of serine/threonine kinases is composed of many isoforms, some of which are expressed in the TAL, including PKC␣, -␤, -␦, -⑀, and - (26,27 the day of the experiment, animals were anesthetized with ketamine (100 mg/kg body weight, intraperitoneally) and xylazine (20 mg/kg body weight, intraperitoneally).…”

mentioning

confidence: 99%