A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase

Ibrahim, Ahmed S.; Elshafey, Sally; Hassan, Sazzad; Hussein, Khaled A.; El-Sherbiny, Mohamed; Abdelsaid, Mohammed; Rizk, Nasser; Beasley, Selina; Tawfik, Amany; Smith, Sylvia B.; Al‐Shabrawey, Mohamed

doi:10.1194/jlr.m056069

Cited by 60 publications

(65 citation statements)

References 45 publications

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“…Type 1 diabetic rat model has shown that retinal capillary cell apoptosis, which precedes the development of histopathology characteristic of diabetic retinopathy, is not observed till 5–6 months of streptozotocin-induced diabetes [30, 31]. Although high circulating glucose is the key instigator, hyperlipidemia is also considered to play an important role in the development of diabetic retinopathy [10–15, 17, 18]. Triglycerides and LDL cholesterol are shown to have a direct correlation with the incidence and severity of diabetic retinopathy, and long-term supplementation with lipid-lowering therapy, fenofibrate, reduces the need for laser treatment in patients with proliferative diabetic retinopathy [12, 14, 32].…”

Section: Discussionmentioning

confidence: 99%

“…Lipid-sensitive Nox2 is activated in the retina during the early stages of diabetes, increasing the levels of cytosolic ROS [9, 10, 17, 18], and increased cytosolic ROS serve as a trigger to damage retinal mitochondria [9, 10, 45]. Our study using in vitro model has shown that the addition of lipotoxic insult in a glucotoxic environment exacerbates cytosolic ROS production and accelerates mitochondrial damage [10].…”

Section: Discussionmentioning

confidence: 99%

“…The results also show that Rac1 is activated before hyperglycemia begins to appear, further confirming the role of Rac1-Nox2 signaling in increased ROS. In support, Rac1-Nox2 signaling is shown to regulate lipid-dependent ROS generation [9, 10, 45], and release of arachidonic acid by activation of phospholipase A2 in hyperglycemia, is implicated in the generation of Nox-mediated ROS [18]. Our data also suggest that the Rac1-Nox2 signaling axis continues to generate ROS, and consistent with the results from the in vitro model in which addition of high glucose in a sustained lipotoxic environment exacerbates ROS levels [10], a temporal relationship is also observed between prolonged hyperlipidemia and increase in retinal Nox2-ROS.…”

Section: Discussionmentioning

confidence: 99%

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Hyperlipidemia and the development of diabetic retinopathy: Comparison between type 1 and type 2 animal models

et al. 2016

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Aim Reactive oxygen species (ROS) are elevated in the retina, and mitochondria are damaged, resulting in capillary cell apoptosis and the development of retinopathy. Dyslipidemia is also considered as one of the major factors in its development, and our aim is to investigate the compounding effect of hyperlipidemia in retinopathy. Methods Retinal ROS, mitochondrial damage and vascular pathology were investigated in Zucker diabetic fatty rats (ZDF, type 2 diabetes model), during the age that spans from hyperlipidemia/pre-hyperglycemia (6 weeks), to severe hyperglycemia/moderate hyperlipidemia (~12 weeks), and ultimately to severe hyperglycemia/hyperlipidemia (20–40 weeks). For comparison, retina from streptozotocin-induced Wistar rats (type 1 diabetic for 10–40 weeks) was analyzed. Results Compared to age-matched lean rats, despite increased retinal cytosolic ROS in 6 weeks old ZDF rats, mitochondrial dysfunction and DNA damage were not detected, and in 12 weeks old ZDF rats, retinal mitochondria were dysfunctional, but mtDNA damage and vascular pathology (cell apoptosis and degenerative capillaries) were not detectable. Retina from 20 weeks old ZDF rats (hyperglycemic for 14 weeks or less) had significant mitochondrial dysfunction, mtDNA damage and vascular pathology, and similar abnormalities were observed in 40 weeks old ZDF rats. Although retinal mitochondrial dysfunction was observed in Wistar rats diabetic for 20 weeks, mtDNA damage and vascular pathology were not detectable till the duration of diabetes was further extended. Conclusions Hyperlipidemia, in a hyperglycemic milieu, potentiates mitochondrial damage and augments the development of retinopathy. Control of dyslipidemia in pre-diabetic patients may prevent/delay the development and the progression of this devastating disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hyperlipidemia and the development of diabetic retinopathy: Comparison between type 1 and type 2 animal models

et al. 2016

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“…Tissues can metabolize fatty acids to biologically active lipid mediators through the cyclooxygenase (COX), lipoxygenase (LOX) or cytochrome P450 epoxygenase (CYP) pathways. While COX, LOX, and their products have received considerable attention in the diabetic retina171819202122232425, relatively little is known about the role of retinal CYP-derived lipid mediators. CYP enzymes are endoplasmic reticulum membrane-bound monooxygenases that oxidize a variety of substrates, including polyunsaturated fatty acids.…”

mentioning

confidence: 99%

Epoxygenated Fatty Acids Inhibit Retinal Vascular Inflammation

Capozzi

Hammer

McCollum

et al. 2016

Sci Rep

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The objective of the present study was to assess the effect of elevating epoxygenated fatty acids on retinal vascular inflammation. To stimulate inflammation we utilized TNFα, a potent pro-inflammatory mediator that is elevated in the serum and vitreous of diabetic patients. In TNFα-stimulated primary human retinal microvascular endothelial cells, total levels of epoxyeicosatrienoic acids (EETs), but not epoxydocosapentaenoic acids (EDPs), were significantly decreased. Exogenous addition of 11,12-EET or 19,20-EDP when combined with 12-(3-adamantane-1-yl-ureido)-dodecanoic acid (AUDA), an inhibitor of epoxide hydrolysis, inhibited VCAM-1 and ICAM-1 expression and protein levels; conversely the diol product of 19,20-EDP hydrolysis, 19,20-DHDP, induced VCAM1 and ICAM1 expression. 11,12-EET and 19,20-EDP also inhibited leukocyte adherence to human retinal microvascular endothelial cell monolayers and leukostasis in an acute mouse model of retinal inflammation. Our results indicate that this inhibition may be mediated through an indirect effect on NFκB activation. This is the first study demonstrating a direct comparison of EET and EDP on vascular inflammatory endpoints, and we have confirmed a comparable efficacy from each isomer, suggesting a similar mechanism of action. Taken together, these data establish that epoxygenated fatty acid elevation will inhibit early pathology related to TNFα-induced inflammation in retinal vascular diseases.

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“…Various other techniques have been optimized such as fundus fluorescein angiography [110], histology and immunohistochemistry for the tight junction components zona occludens 1 (ZO-1 = tight junction protein 1 or TJP1), claudin-5 and occludin [111,112]; quantitative fluorophotometry in rat eye [113][114][115][116] and OCT thickness measurements [116,117]. Thus, most of the techniques are focused on determining the vascular complications in the hyperglycemic eyes of STZ mice and rats.…”

Section: Diabetic Modelsmentioning

confidence: 99%

Selection Strategy of In Vivo Models for Ophthalmic Drug Development in Diabetic Retinopathy

Geert¹,

Tjing-Tjing²

2016

J Mol Genet Med

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Diabetic Retinopathy (DR) is the most common microvascular complication of diabetes and is one of the leading causes of visual impairment worldwide. DR is a chronic eye disease that eventually can result in legal blindness due to the evolution towards the major vision-threatening disorders diabetic macular edema (DME) and/or proliferative diabetic retinopathy (PDR). Current treatments with steroids, anti-VEGF compounds or retinal laser photocoagulation have shown a significant improvement in visual acuity in the advanced stage of the disease. However, main concerns are possible side effects and/or the relatively large number of clinical non-responders. A better understanding of the biological and molecular pathways not only in DR patients but also in the preclinical in vivo models would aid the development of novel and more efficient (personalized) therapeutic approaches for DR. This review aims to describe the pathways in a selection of diabetic, non-diabetic and surrogate rodent models of pathogenic neovascularization, vascular permeability, inflammation and neurodegeneration. None of these models can mimic the entire human pathophysiological progression but they all exhibit joint pathophysiological features with human DR pathogenesis. These combined features make these models very relevant in gaining a better understanding of the disease etiology and eventually improved strategies for drug screening. Through highlighting the most important biochemical and molecular pathways that these animal models have in common with DR patients, selection of the most suitable model for mechanistic studies and drug screening can be facilitated.

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A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase

Cited by 60 publications

References 45 publications

Hyperlipidemia and the development of diabetic retinopathy: Comparison between type 1 and type 2 animal models

Hyperlipidemia and the development of diabetic retinopathy: Comparison between type 1 and type 2 animal models

Epoxygenated Fatty Acids Inhibit Retinal Vascular Inflammation

Selection Strategy of In Vivo Models for Ophthalmic Drug Development in Diabetic Retinopathy

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