Abstract
Hyperglycemia-induced impairment of the blood-retinal barrier represents the main pathological event in diabetic retinopathy that is elicited by a reduced cellular response to an accumulation of reactive oxygen species (ROS) and increased inflammation. The purpose of the study was to evaluate whether the selective β1-adrenoreceptor (β1-AR) antagonist metoprolol could modulate the inflammatory response to hyperglycemic conditions. For this purpose, human retinal endothelial cells (HREC) were treated with normal (5 mM) or high glucose (25 mM, HG) in the presence of metoprolol (10 μM), epinephrine (1 μM), or both compounds. Metoprolol prevented both the HG-induced reduction of cell viability (MTT assays) and the modulation of the angiogenic potential of HREC (tube formation assays) reducing the TNF-α, IL-1β, and VEGF mRNA levels (qRT-PCR). Moreover, metoprolol prevented the increase in phospho-ERK1/2, phospho-cPLA2, COX2, and protein levels (Western blot) as well as counteracting the translocation of ERK1/2 and cPLA2 (high-content screening). Metoprolol reduced ROS accumulation in HG-stimulated HREC by activating the anti-oxidative cellular response mediated by the Keap1/Nrf2/HO-1 pathway. In conclusion, metoprolol exerted a dual effect on HG-stimulated HREC, decreasing the activation of the pro-inflammatory ERK1/2/cPLA2/COX2 axis, and counteracting ROS accumulation by activating the Keap1/Nrf2/HO-1 pathway.
Highlights
Diabetic retinopathy (DR), a major cause of blindness, interrupts the physiological interaction between the vascular and neural components of the retina, causing vascular permeability, neovascularization, loss of the blood–retinal barrier (BRB) and, the loss of proper visual function [1]
We examined the effects of the β-AR antagonist metoprolol and the β-AR agonist epinephrine on human retinal endothelial cells (HREC) that were treated with a high glucose concentration in a model mimicking the processes that occur in proliferative retinopathy phases
Since the data that were obtained showed that the β1-AR blockade could prevent vascular remodeling as well as the activation of the pro-inflammatory ERK1/2/cPLA2 /COX2 pathway induced by HG in HREC, we aimed to investigate whether the metoprolol effects could cause a modulation of tumor necrosis factor-α (TNF-α), IL-1β, and vascular endothelial growth factor (VEGF) mRNA levels in HREC that was treated with NG (5 mM) or HG (25 mM) with or without 10 μM of metoprolol
Summary
Diabetic retinopathy (DR), a major cause of blindness, interrupts the physiological interaction between the vascular and neural components of the retina, causing vascular permeability, neovascularization, loss of the blood–retinal barrier (BRB) and, the loss of proper visual function [1]. A meta-analysis that analyzed published and unpublished population-based data for the causes of vision impairment and blindness between. In the initial phase, defined as non-proliferative, DR is characterized by an increase in vascular permeability and by the onset of microaneurysms and hemorrhage. At the most advanced stage, DR is characterized by neovascularization and is called proliferative DR. During this phase, new, abnormal blood vessels are created [3] and patients have severe vision impairment [4]. Some patients benefit from anti-vascular endothelial growth factor (VEGF) therapy, most patients fail to achieve clinically meaningful visual improvement and DR treatment remains challenging [4,5]
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