Effect of NADPH oxidase 1 and 4 blockade in activated human retinal endothelial cells

Appukuttan, Binoy; Ma, Yuefang; Stempel, Andrew J.; Ashander, Liam M.; Deliyanti, Devy; Wilkinson-Berka, Jennifer L; Smith, Justine R.

doi:10.1111/ceo.13155

Cited by 26 publications

(24 citation statements)

References 44 publications

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“…The isoforms, NOX1, NOX2, NOX4, and NOX5 were found in endothelial cells. In the retina, NOX1, NOX2, and NOX4 are the most well-studied isoforms [ 74 , 75 , 76 , 77 , 78 ]. NOX2, known as gp91phox, was the first NOX isoform to be identified and the most studied one in the research field of DR [ 79 ].…”

Section: Pathophysiological Role Of Ros In the Retinal Vasculaturementioning

confidence: 99%

“…Blockade of NOX4 by the NOX4 inhibitors, GKT136901 and GKT137831, significantly reduced ROS levels and cell death in retinal endothelium. Hence, NOX4 may be considered as a potential therapeutic target in patients with retinal vascular diseases [ 78 ].…”

Section: Pathophysiological Role Of Ros In the Retinal Vasculaturementioning

confidence: 99%

“…The NOX4 inhibitors, GKT136901 and GKT137831, developed by GenKyoTex, are the best characterized NOX4 inhibitors currently available [ 244 ]. In experimental models of retinal vasculopathy by Appukuttan et al, GKT136901 and GKT137831 significantly reduced ROS generation and VEGF-A expression in retinal endothelial cells by inhibiting dimethyloxalylglycine (DMOG), which supported the therapeutic strategies of NOX4 inhibitors (GKT136901 and GKT137831) in retinal vascular diseases [ 78 ]. In a rat model of ischemic retinopathy, GKT137831 was shown to reduce inflammation by downregulating the pro-inflammatory phenotype of microglia [ 245 ].…”

Section: Therapeutic Strategies To Reduce Oxidative Stressmentioning

confidence: 99%

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Oxidative Stress and Vascular Dysfunction in the Retina: Therapeutic Strategies

et al. 2020

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Many retinal diseases, such as diabetic retinopathy, glaucoma, and age-related macular (AMD) degeneration, are associated with elevated reactive oxygen species (ROS) levels. ROS are important intracellular signaling molecules that regulate numerous physiological actions, including vascular reactivity and neuron function. However, excessive ROS formation has been linked to vascular endothelial dysfunction, neuron degeneration, and inflammation in the retina. ROS can directly modify cellular molecules and impair their function. Moreover, ROS can stimulate the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) causing inflammation and cell death. However, there are various compounds with direct or indirect antioxidant activity that have been used to reduce ROS accumulation in animal models and humans. In this review, we report on the physiological and pathophysiological role of ROS in the retina with a special focus on the vascular system. Moreover, we present therapeutic approaches for individual retinal diseases targeting retinal signaling pathways involving ROS.

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Section: Pathophysiological Role Of Ros In the Retinal Vasculaturementioning

confidence: 99%

Section: Pathophysiological Role Of Ros In the Retinal Vasculaturementioning

confidence: 99%

Section: Therapeutic Strategies To Reduce Oxidative Stressmentioning

confidence: 99%

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Oxidative Stress and Vascular Dysfunction in the Retina: Therapeutic Strategies

et al. 2020

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“…Furthermore, we showed that GPER opposed the effects of Ang II by downregulating Nox4 at the transcriptional level and restoring catalase activity. These findings have important implications since randomized clinical trials fail to significantly inhibit oxidative stress using currently available antioxidants such as vitamin E (41–43), while preclinical studies with Nox1 and 4 inhibitors (44, 45) are promising. Since oxidative stress is detrimental to cardiovascular tissues, GPER may provide a novel target for inhibition of vascular ROS.…”

Section: Discussionmentioning

confidence: 99%

G Protein-Coupled Estrogen Receptor Protects From Angiotensin II-Induced Increases in Pulse Pressure and Oxidative Stress

et al. 2019

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Our previous work showed that the G protein-coupled estrogen receptor (GPER) is protective in the vasculature and kidneys during angiotensin (Ang) II-dependent hypertension by inhibiting oxidative stress. The goal of the current study was to assess the impact of GPER deletion on sex differences in Ang II-induced hypertension and oxidative stress. Male and female wildtype and GPER knockout mice were implanted with radiotelemetry probes for measurement of baseline blood pressure before infusion of Ang II (700 ng/kg/min) for 2 weeks. Mean arterial pressure was increased to the same extent in all groups, but female wildtype mice were protected from Ang II-induced increases in pulse pressure, aortic wall thickness, and Nox4 mRNA. In vitro studies using vascular smooth muscle cells found that pre-treatment with the GPER agonist G-1 inhibited Ang II-induced ROS and NADP/NADPH. Ang II increased while G-1 decreased Nox4 mRNA and protein. The effects of Ang II were blocked by losartan and Nox4 siRNA, while the effects of G-1 were inhibited by adenylyl cyclase inhibition and mimicked by phosphodiesterase inhibition. We conclude that during conditions of elevated Ang II, GPER via the cAMP pathway suppresses Nox4 transcription to limit ROS production and prevent arterial stiffening. Taken together with our previous work, this study provides insight into how acute estrogen signaling via GPER provides cardiovascular protection during Ang II hypertension and potentially other diseases characterized by increased oxidative stress.

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“…Tellios et al 7 used primary human trabecular meshwork cells to show that the gap junction protein, connexin43, may be a marker of trabecular meshwork stretch‐related injury in primary open‐angle glaucoma. Appukuttan et al 8 worked with primary retinal vascular endothelial cells, as well as cells that were immortalized by transfection with human papillomavirus genes, to study novel inhibitors of enzymes that produce reactive oxygen species, with implications for the treatment of retinal vascular diseases. In addition, human ocular tissue may be grown in the dish or dissected fresh from human eyes for research projects.…”

mentioning

confidence: 99%

Translational research in ophthalmology

Smith

2020

Clinical Exper Ophthalmology

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Effect of NADPH oxidase 1 and 4 blockade in activated human retinal endothelial cells

Cited by 26 publications

References 44 publications

Oxidative Stress and Vascular Dysfunction in the Retina: Therapeutic Strategies

Oxidative Stress and Vascular Dysfunction in the Retina: Therapeutic Strategies

G Protein-Coupled Estrogen Receptor Protects From Angiotensin II-Induced Increases in Pulse Pressure and Oxidative Stress

Translational research in ophthalmology

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