S-Nitrosoglutathione Inhibits Inducible Nitric Oxide Synthase Upregulation by Redox Posttranslational Modification in Experimental Diabetic Retinopathy

Rosales, Mariana A. B.; Silva, Kamila C.; Duarte, Diego Andreazzi; Oliveira, Marcelo Ganzarolli de; Souza, Gabriela Freitas Pereira de; Catharino, Rodrigo Ramos; Ferreira, Mônica Siqueira; Faria, José B. Lopes de; Faria, Jacqueline M. Lopes de

doi:10.1167/iovs.13-13762

Cited by 22 publications

(14 citation statements)

References 49 publications

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“…In addition, liraglutide was able to prevent the diabetes-induced increase of caspase-8 and the Bax (proapoptotic)/Bcl-xL (antiapoptotic) ratio. In addition, we found that liraglutide (systemically and topically administered) was able to prevent the diabetes-induced retinal activation of p53, a factor that participates in hypoxic and oxidative stress-mediated retinal cell death (38), as well as several key molecules involved in retinal apoptosis and inflammation such as FasL and iNOS (39)(40)(41).…”

Section: Discussionmentioning

confidence: 94%

Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes

et al. 2015

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Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). Since glucagonlike peptide 1 (GLP-1) exerts neuroprotective effects in the central nervous system and the retina is ontogenically a brain-derived tissue, the aims of the current study were as follows: 1) to examine the expression and content of GLP-1 receptor (GLP-1R) in human and db/db mice retinas; 2) to determine the retinal neuroprotective effects of systemic and topical administration (eye drops) of GLP-1R agonists in db/db mice; and 3) to examine the underlying neuroprotective mechanisms. We have found abundant expression of GLP-1R in the human retina and retinas from db/db mice. Moreover, we have demonstrated that systemic administration of a GLP-1R agonist (liraglutide) prevents retinal neurodegeneration (glial activation, neural apoptosis, and electroretinographical abnormalities). This effect can be attributed to a significant reduction of extracellular glutamate and an increase of prosurvival signaling pathways. We have found a similar neuroprotective effect using topical administration of native GLP-1 and several GLP-1R agonists (liraglutide, lixisenatide, and exenatide). Notably, this neuroprotective action was observed without any reduction in blood glucose levels. These results suggest that GLP-1R activation itself prevents retinal neurodegeneration. Our results should open up a new approach in the treatment of the early stages of DR.

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Section: Discussionmentioning

confidence: 94%

Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes

et al. 2015

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“…In addition, iNOS serves an important role in leukostasis, apoptosis and BRB breakdown (27,28). Concurrently, white blood cells interact with, and bind to, ICAM-1 on the surface of endothelial cells in a multi-step process leading to adherence of the blood cells to the endothelial wall.…”

Section: Discussionmentioning

confidence: 99%

Niaspan inhibits diabetic retinopathy-induced vascular inflammation by downregulating the tumor necrosis factor-α pathway

Wang

Meng

Yan

2017

Molecular Medicine Reports

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Diabetic retinopathy (DR) is a serious microvascular complication of diabetes and a major cause of blindness in the developing world. Early DR is characterized by vascular neuroinflammation, cell apoptosis and breakdown of the blood-retinal barrier (BRB). However, optimal treatment options and associated mechanisms remain unclear. Niaspan, which is widely used in the prevention and treatment of hyperlipidemia-associated diseases, has been reported to inhibit inflammation. However, the effects of Niaspan and the mechanisms underlying the anti-inflammatory effects of Niaspan on DR have yet to be reported. The present study aimed to investigate the anti-inflammatory effects and mechanisms of Niaspan in a rat model of DR. Rats with DR exhibited a significant increase in BRB breakdown, retinal apoptosis, and tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB) expression. In addition, the expression levels of inducible nitric oxide synthase (iNOS) and intercellular cell adhesion molecule-1 (ICAM-1) were increased in the retinas of DR rats compared with in the normal control group. In conclusion, treatment with Niaspan significantly improved clinical and histopathological outcomes; decreased the expression levels of TNF-α, NF-κB, iNOS and ICAM-1; and decreased apoptosis and BRB breakdown, as compared with in the retinas of DR rats. The present study is the first, to the best of our knowledge, to demonstrate that Niaspan treatment ameliorates DR by inhibiting inflammation, and also suggests that the TNF-α pathway may contribute to the beneficial effects of Niaspan treatment.

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“…Recent studies suggested inverse relationship between HO-1 and iNOS expression, where restoring HO-1 or carbon monoxide inhibits iNOS expression [31,32]. There is increasing evidence that iNOS is anti-angiogenic [18].…”

Section: Discussionmentioning

confidence: 99%

Candesartan stimulates reparative angiogenesis in ischemic retinopathy model: role of hemeoxygenase-1 (HO-1)

et al. 2014

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Ischemic diseases such as stroke and proliferative retinopathy are characterized by hypoxia-driven release of angiogenic factors such as vascular endothelial growth factor (VEGF). However, revascularization of the ischemic areas is inadequate resulting in impaired neuro-vascular function. We aim to examine the vascular protective effects of candesartan, an angiotensin receptor blocker, in an ischemic retinopathy mouse model. Vascular density, number of tip cells, and perfusions of capillaries were assessed. Activation of Muller glial cells and levels of peroxynitrite, VEGF, VEGFR2, inducible- nitric oxide synthase, hemoxygenase-1 (HO-1) were assessed. Proangiogenic effects of candesartan were examined in human endothelial cells (EC) that were cultured in normoxia or hypoxia and transduced with siRNA against HO-1. Candesartan (1mg/kg) and (10mg/kg) decreased hypoxia-induced neovascularization by 67% and 70%, respectively. Candesartan (10mg/kg) significantly stimulated the number of tip cells and physiological revascularization of the central retina (45%) compared to untreated pups. The effects of candesartan coincided with reduction of hypoxia-induced Muller glial activation, iNOS expression and restoration of HO-1 expression with no significant change in VEGF levels. In vitro, silencing HO-1 expression blunted the ability of candesartan to induce VEGF expression under normoxia and VEGFR2 activation and angiogenic response under both normoxia and hypoxia. These findings suggest that candesartan improved reparative angiogenesis and hence prevented pathological angiogenesis by modulating HO-1 and iNOS levels in ischemic retinopathy. HO-1 is required for VEGFR2 activation and proangiogenic action of candesartan in EC. Candesartan, an FDA-approved drug could be repurposed as a potential therapeutic agent for the treatment of ischemic diseases.

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S-Nitrosoglutathione Inhibits Inducible Nitric Oxide Synthase Upregulation by Redox Posttranslational Modification in Experimental Diabetic Retinopathy

Cited by 22 publications

References 49 publications

Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes

Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes

Niaspan inhibits diabetic retinopathy-induced vascular inflammation by downregulating the tumor necrosis factor-α pathway

Candesartan stimulates reparative angiogenesis in ischemic retinopathy model: role of hemeoxygenase-1 (HO-1)

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