Thrombosis and Hemorrhage in Diabetic Retinopathy: A Perspective from an Inflammatory Standpoint

Murugesan, Nivetha; Üstünkaya, Tuna; Feener, Edward P.

doi:10.1055/s-0035-1556731

Cited by 38 publications

(27 citation statements)

References 44 publications

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“…TM, via thrombin-mediated activation of protein C and TAFI, provides protection against inflammation. Thrombin is an important inflammatory factor in retinal vascular diseases including DR 41 . It was reported that thrombin and prothrombin were increased in the vitreous of patients with proliferative DR compared with nondiabetic individuals 42 .…”

Section: Discussionmentioning

confidence: 99%

PPARα activation directly upregulates thrombomodulin in the diabetic retina

Shiono

Sasaki

Sekine

et al. 2020

Sci Rep

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Two large clinical studies showed that fenofibrate, a commonly used peroxisome proliferatoractivated receptor α (PPARα) agonist, has protective effects against diabetic retinopathy. However, the underlying mechanism has not been clarified. We performed genome-wide analyses of gene expression and PPARα binding sites in vascular endothelial cells treated with the selective PPARα modulator pemafibrate and identified 221 target genes of PPARα including THBD, which encodes thrombomodulin (TM). ChIP-qPCR and luciferase reporter analyses showed that PPARα directly regulated THBD expression via binding to the promoter. In the rat diabetic retina, treatment with pemafibrate inhibited the expression of inflammatory molecules such as VCAM-1 and MCP1, and these effects were attenuated by intravitreal injection of small interfering RNA targeted to THBD. Furthermore, pemafibrate treatment inhibited diabetes-induced vascular leukostasis and leakage through the upregulation of THBD. Our results indicate that PPARα activation inhibits inflammatory and vasopermeable responses in the diabetic retina through the upregulation of TM. Diabetic retinopathy (DR) is the main cause of blindness among working-age adults, and the worldwide prevalence is approximately 35% in patients with diabetes 1. DR is characterized by the combination of increased vessel permeability and progressive vascular occlusion. However, the molecular mechanisms underlying the pathways associated with DR have not been fully elucidated. Several biochemical mechanisms have been proposed to modulate the pathogenesis of DR through effects on cellular metabolism, signaling, and growth factors 2. Implicated pathways include the accumulation of sorbitol and advanced glycation end-products, oxidative stress, protein kinase C activation, and upregulation of the renin-angiotensin system and vascular endothelial growth factor (VEGF). Among them, VEGF strongly promotes angiogenesis, a key mediator of the progression of DR. Inhibition of VEGF (e.g., anti-VEGF therapies) was shown to be effective in the management of DR in numerous studies 3-7. However, some DR patients respond poorly or incompletely to anti-VEGF therapy. Accordingly, there is still substantial unmet medical need in patients with DR. Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that regulates lipid metabolism 8. PPARα is highly expressed in the liver and is also expressed in the retina 9. Recently, two large, prospective clinical trials have demonstrated that fenofibrate, a canonical synthetic PPARα agonist, has protective effects against DR in type 2 diabetes patients. The Fenofibrate Intervention in Event Lowering in Diabetes (FIELD) Study reported that fenofibrate therapy significantly reduced the cumulative need for laser therapy for DR 10. The Action Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study of combination simvastatin and fenofibrate demonstrated a greater reduction in the progression of proliferative DR in type 2 diabetes patients compar...

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Section: Discussionmentioning

confidence: 99%

PPARα activation directly upregulates thrombomodulin in the diabetic retina

Shiono

Sasaki

Sekine

et al. 2020

Sci Rep

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“…Besides inflammation and apoptosis, platelet adhesion is also involved in diabetes-induced retinal endothelial dysfunction 93 . The platelet adhesion to the injured diabetic endothelium takes part in ischemia and inflammation, both coagulation and fibrinolytic cascades in the vitreous are identified in DR 114 . Blood platelets tend to adhere to the vascular endothelium of DR rather than normal vessels 115 , which is involved in retinal capillaries occlusion and microvascular damage.…”

Section: Generation Of H2s In Ocular Tissuesmentioning

confidence: 99%

Hydrogen sulfide: a gaseous signaling molecule modulates tissue homeostasis: implications in ophthalmic diseases

et al. 2019

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Hydrogen sulfide (H 2 S) serves as a gasotransmitter in the regulation of organ development and maintenance of homeostasis in tissues. Its abnormal levels are associated with multiple human diseases, such as neurodegenerative disease, myocardial injury, and ophthalmic diseases. Excessive exposure to H 2 S could lead to cellular toxicity, orchestrate pathological process, and increase the risk of various diseases. Interestingly, under physiological status, H 2 S plays a critical role in maintaining cellular physiology and limiting damages to tissues. In mammalian species, the generation of H 2 S is catalyzed by cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE), 3-mercapto-methylthio pyruvate aminotransferase (3MST) and cysteine aminotransferase (CAT). These enzymes are found inside the mammalian eyeballs at different locations. Their aberrant expression and the accumulation of substrates and intermediates can change the level of H 2 S by orders of magnitude, causing abnormal structures or functions in the eyes. Detailed investigations have demonstrated that H 2 S donors’ administration could regulate intraocular pressure, protect retinal cells, inhibit oxidative stress and alleviate inflammation by modulating the function of intra or extracellular proteins in ocular tissues. Thus, several slow-releasing H 2 S donors have been shown to be promising drugs for treating multiple diseases. In this review, we discuss the biological function of H 2 S metabolism and its application in ophthalmic diseases.

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“…More than 50% of patients with diabetes experience retinopathy, of which 1%–2% become blind as a result (Moraes & Layton, 2016). The pathogenesis of DR remains unclear, however, several studies have implicated apoptosis, inflammation, and oxidation (Mrugacz & Bossowski, 2016; Murugesan et al., 2015; Tong et al., 2019).…”

Section: Introductionmentioning

confidence: 99%

Hawthorn polyphenols reduce high glucose‐induced inflammation and apoptosis in ARPE‐19 cells by regulating miR‐34a/SIRT1 to reduce acetylation

Liu

Fang

et al. 2021

J. Food Biochem.

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Diabetic retinopathy is a major complication in patients with diabetes. Herein, we investigate how hawthorn polyphenol extract (HPE) affects high glucose-induced oxidation, inflammation, and apoptosis in ARPE-19 cells. HPLC-MS/MS was used to determine HPE content and composition. Reactive oxygen species (ROS) production was assessed using fluorescence microscopy, while glucose-induced gene and protein expressions were analyzed using real-time PCR and western blotting in cells transfected with miR-34a mimics. We found that treating cells with 10 μg/ml of HPE, 30 μM procyanidin B2, chlorogenic acid, epicatechin, or resveratrol (positive control) significantly reduced ROS production and decreased apoptosis and inflammationrelated factors (p < .01). Moreover, the expression level of SIRT1 was increased, while that of acetylated NF-κB p65 and p53 proteins was decreased. These data suggest that HPE can inhibit oxidative damage, inflammation, and apoptosis through the AMPK/SIRT1/NF-κB pathway, and decrease miR-34a/SIRT1/p53 pathway activation in ARPE-19 cells, thereby demonstrating a potential use as a food additive to mitigate hyperglycemia-induced retinal damage. Practical applications Hawthorn polyphenol extract (HPE) significantly reduced ROS levels, apoptosis, and the expression of inflammation-related factors in ARPE-19 cells. HPE also inhibited the AMPK/SIRT1/NF-κB and miR-34a/SIRT1/p53 pathways, which are involved in hyperglycemia-induced inflammation and apoptosis of ARPE-19 cells by regulating acetylation. Thus, HPE, as a potential food additive, may mitigate hyperglycemiainduced retinal damage.

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Thrombosis and Hemorrhage in Diabetic Retinopathy: A Perspective from an Inflammatory Standpoint

Cited by 38 publications

References 44 publications

PPARα activation directly upregulates thrombomodulin in the diabetic retina

PPARα activation directly upregulates thrombomodulin in the diabetic retina

Hydrogen sulfide: a gaseous signaling molecule modulates tissue homeostasis: implications in ophthalmic diseases

Hawthorn polyphenols reduce high glucose‐induced inflammation and apoptosis in ARPE‐19 cells by regulating miR‐34a/SIRT1 to reduce acetylation

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