Hypoxia-Induced Oxidative Stress in Ischemic Retinopathy

Li, Suk-Yee; Fu, Zhongjie; Lo, Amy Cheuk Yin

doi:10.1155/2012/426769

Cited by 111 publications

(95 citation statements)

References 103 publications

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“…SOD provides a cellular defense mechanism by scavenging ROS, which constitutes one of the major defense mechanisms of cells against OS (29). In pathological conditions, such as hypoxia, excessive ROS interact with cellular proteins, lipids and DNA, resulting in oxidative cell and tissue damage, and/or behave as second messengers, promoting pulmonary vascular remodeling (30).…”

Section: Discussionmentioning

confidence: 99%

Effects of 17β-estradiol and 2-methoxyestradiol on the oxidative stress-hypoxia inducible factor-1 pathway in hypoxic pulmonary hypertensive rats

Wang

Zheng

Yuan

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. The present study aimed to investigate the effects of 17β-estradiol (E2) and 2-methoxyestradiol (2ME) on the oxidative stress-hypoxia inducible factor-1 (OS-HIF-1) pathway in hypoxic pulmonary hypertensive rats. Female Sprague-Dawley rats were divided randomly into 4 groups, as follows: i) Control (Group A); ii) ovariectomy (OVX) + hypoxia (Group B); iii) OVX + hypoxia + E2 injection (Group C); and iv) 2ME injection (Group D). The rats were maintained under hypoxic conditions for 8 weeks, and mean pulmonary artery pressure (mPAP) and pulmonary arteriole morphology were measured. The reactive oxygen species, superoxide dismutase (SOD), manganese superoxide dismutase (MnSOD), and copper-zinc superoxide dismutase (Cu/ZnSOD) levels in serum were also measured. MnSOD and HIF-1α expression levels in lung tissue were determined by western blotting and reverse transcription-quantitative polymerase chain reaction. The mPAP and arterial remodeling index were significantly elevated following chronic hypoxia exposure; however, experimental data revealed a reduced response in E2 and 2ME intervention rats. Compared with Group A, Group B had significantly elevated oxidative stress levels, as illustrated by increased serum ROS levels, decreased serum SOD and MnSOD levels and decreased MnSOD mRNA and protein expression levels in lung tissue. Furthermore, HIF-1α mRNA and protein expression in Group B was significantly elevated compared with Group A. E2 and 2ME intervention significantly attenuated the aforementioned parameter changes, suggesting that E2 and 2ME partially ameliorate hypoxic pulmonary hypertension. The underlying mechanism of this may be associated with the increase in MnSOD activity and expression and reduction in ROS level, which reduces the levels of transcription and translation of HIF-1α.

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Section: Discussionmentioning

confidence: 99%

Effects of 17β-estradiol and 2-methoxyestradiol on the oxidative stress-hypoxia inducible factor-1 pathway in hypoxic pulmonary hypertensive rats

Wang

Zheng

Yuan

et al. 2017

Experimental and Therapeutic Medicine

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“…23 Ischemia thus plays a pathological role in many eye diseases including ROP, glaucoma, central vein occlusion, retinal detachment, and AMD. 23,[44][45][46] Further, hypoxic oxidative stress contributes to neurodegeneration in many of these models. 23 Our present findings suggest that PPARa also has significant therapeutic potential in these ischemic retinal diseases, much as in DR.…”

Section: Discussionmentioning

confidence: 99%

“…[18][19][20][21][22] Hypoxia's pathological effect in DR is complex, but is due in part to oxidative stress, namely increased reactive oxygen species (ROS) production. 15,23,24 Many mechanisms contribute to hypoxic oxidative stress, including upregulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family proteins. 25 Nicotinamide adenine dinucleotide phosphate oxidases possess a catalytic NADPH oxidase (Nox) subunit, which generates ROS by catalyzing electron transport from NADPH to molecular oxygen, thus producing superoxide.…”

Section: Methodsmentioning

confidence: 99%

Protective and Antioxidant Effects of PPARα in the Ischemic Retina

Moran

Ding

Wang

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Previous studies have demonstrated that peroxisome proliferator-activated receptoralpha (PPARa) agonists have therapeutic effects in diabetic retinopathy, although the mechanism of action remains incompletely understood. The purpose of this study was to evaluate PPARa's protective effects in the ischemic retina, and to delineate its molecular mechanism of action. METHODS.For the oxygen-induced retinopathy (OIR) model, wild-type (WT), and PPARa knockout (PPARa À/À ) mice were exposed to 75% O 2 from postnatal day 7 (P7) to P12 and treated with the PPARa agonist fenofibric acid (Feno-FA) from P12 to P16. At P17, the effects of Feno-FA on retinal glial fibrillary acidic protein (GFAP) expression, apoptotic DNA cleavage, and TUNEL labeling were analyzed. Cultured retinal cells were exposed to CoCl 2 to induce hypoxia, and TUNEL staining and 5-(and-6)-chloromethyl-2 0 ,7 0 -dichlorodihydrofluorescein dye were used to measure apoptosis and reactive oxygen species (ROS) generation. Western blotting was used to measure GFAP levels and cell signaling. RESULTS. Feno-FA decreased retinal apoptosis and oxidative stress in WT but not PPARaÀ/À OIR mice. Peroxisome proliferator-activated receptor-alpha knockout OIR mice showed increased retinal cell death and glial activation in comparison to WT OIR mice. Feno-FA treatment and PPARa overexpression protected cultured retinal cells from hypoxic cell death and decreased ROS levels. Nuclear hypoxia-inducible factor-a (HIF-1a) and nicotine adenine dinucleotide phosphate oxidase-4 (Nox 4) were increased in OIR retinas and downregulated by Feno-FA in WT but not in PPARa À/À mice.CONCLUSIONS. Peroxisome proliferator-activated receptor-alpha has a potent antiapoptotic effect in the ischemic retina. This protective effect may be mediated in part through downregulation of HIF-1a/Nox 4 and consequently alleviation of oxidative stress.

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“…Excess extracellular release of glutamate is known to kill neurons by excitotoxic mechanisms through activation the NMDA and AMPA receptors. Excitotoxicity has been suggested as a major mechanism underlying RGC death in many ocular pathologies including diabetic retinopathy, retinal and choroidal vessels occlusion and glaucoma [95][96][97][98][99][100]. Excitotoxic neuronal death involves calcium influx into the cells [101] that has been reported as an essential component of glutamate neurotoxicity [102].…”

Section: Hypoxia and Glutamatementioning

confidence: 99%

Cellular and Molecular Mechanisms of Retinal Ganglion Cell Death in Hypoxic-Ischemic Injuries

Kaur¹,

Rathnasamy²,

Foulds³

et al. 2015

J Neurol Exp Neurosci

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Loss of retinal ganglion cells (RGCs) occurs in retinal degenerative diseases, such as glaucoma, age-related macular degeneration, diabetic retinopathy, central retinal artery occlusion and ischemic central retinal vein thrombosis in adults and in retinopathy of prematurity in infants. A critical role of hypoxia, which underlies most of the above disorders, has been reported in causing RGC death. Disruption of blood-retinal barrier (BRB) occurs due to increased production of vascular endothelial growth factor and nitric oxide in response to hypoxia resulting in extravasation of serum derived substances and retinal edema and this may be one of important factors mediating RGC death. Activation of microglial cells in response to hypoxia and subsequent increased release of proinflammatory cytokines by them such as tumor-necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) target the TNF-receptor 1 and IL-receptor 1 on RGCs. Excess release of glutamate in retinal tissue under hypoxia activates the ionotropic glutamate receptors causing excitotoxicity through increased influx of calcium into the RGCs. Increased production of TNF-α, IL-1β and enhanced intracellular calcium results in RGC death through activating several pathways such as caspase signaling, mitochondrial dysfunction and oxidative stress. In our investigations, melatonin, an antioxidant, was shown to reduce RGC death in the adult and neonatal hypoxic retina, through suppression of TNF-α, IL-1β and glutamate levels as well as oxidative stress. Moreover, the function and structure of BRB was well preserved in these animals along with reduction in retinal edema. In view of our observations, we suggest that melatonin could be considered as a therapeutic agent to reduce RGC death in various retinal pathologies, in addition to other potential drugs/molecules of therapeutic interest that could render protection to RGCs. However, future in-depth research on the effects of melatonin on the retina under hypoxic conditions needs to be undertaken to explore its full potential in preventing/ameliorating RGC death. Factors Mediating RGC DeathSeveral factors induced or upregulated by hypoxia may be involved in causing RGC death. These factors include, among others, disruption of the blood-retinal barrier, activation of microglial cells and the accompanying enhanced release of inflammatory cytokines and excess release and accumulation of glutamate in the retinal tissues. Hypoxia and the blood-retinal barrierThe BRB regulates the passage of molecules from blood into the retina [11,12]. It consists of an inner BRB formed by the tight junctions (TJ) between capillary endothelial cells and an outer barrier formed by TJ between retinal pigment epithelial cells [12][13][14][15][16]. The TJ are made up of transmembrane proteins such as occludin, claudin-5 and cytoplasmic proteins such as zona occludens (ZO)-1 that are structurally and functionally important for maintaining the integrity of the BRB. The proper functioning of the inner BRB also requires the collective co...

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Hypoxia-Induced Oxidative Stress in Ischemic Retinopathy

Cited by 111 publications

References 103 publications

Effects of 17β-estradiol and 2-methoxyestradiol on the oxidative stress-hypoxia inducible factor-1 pathway in hypoxic pulmonary hypertensive rats

Effects of 17β-estradiol and 2-methoxyestradiol on the oxidative stress-hypoxia inducible factor-1 pathway in hypoxic pulmonary hypertensive rats

Protective and Antioxidant Effects of PPARα in the Ischemic Retina

Cellular and Molecular Mechanisms of Retinal Ganglion Cell Death in Hypoxic-Ischemic Injuries

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