Effect of troxerutin in counteracting hyperglycemia-induced VEGF upregulation in endothelial cells: a new option to target early stages of diabetic retinopathy?

Abstract

Diabetic retinopathy (DR), one of the most common complications of diabetes mellitus, is characterized by degeneration of retinal neurons and neoangiogenesis. Until today, the pharmacological approaches for DR are limited and focused on counteracting the end-stage of this neurodegenerative disease, therefore efforts should be carried out to discover novel pharmacological targets useful to prevent DR development. Hyperglycemia is a major risk factor for endothelial dysfunction and vascular complication, which subsequently may trigger neurodegeneration. We previously demonstrated that, in the rat retina, hyperglycemia activates a new molecular cascade implicating, up-stream, protein kinase C βII (PKC βII), which in turn leads to a higher expression of vascular endothelial growth factor (VEGF), via the mRNA-binding Hu-antigen R (HuR) protein. VEGF is a pivotal mediator of neovascularization and a well-known vasopermeability factor. Blocking the increase of VEGF via modulation of this cascade can thus represent a new pharmacological option to prevent DR progression. To this aim, proper in vitro models are crucial for drug discovery, as they allow to better identify promising effective molecules. Considering that endothelial cells are key elements in DR and that hyperglycemia triggers the PKCβII/HuR/VEGF pathway, we set up two distinct in vitro models applying two different stimuli. Namely, human umbilical vein endothelial cells were exposed to phorbol 12-myristate 13-acetate, which mimics diacylglycerol whose synthesis is triggered by diabetic hyperglycemia, while human retinal endothelial cells were treated with high glucose for different times. After selecting the optimal experimental conditions able to determine an increased VEGF production, in search of molecules useful to prevent DR development, we investigated the capability of troxerutin, an antioxidant flavonoid, to counteract not only the rise of VEGF but also the activation of the PKCβII/HuR cascade in both in vitro models. The results show the capability of troxerutin to hinder the hyperglycemia-induced increase in VEGF in both models through PKCβII/HuR pathway modulation. Further, these data confirm the key engagement of this cascade as an early event triggered by hyperglycemia to promote VEGF expression. Finally, the present findings also suggest the potential use of troxerutin as a preventive treatment during the early phases of DR.

Diabetic vascular diseases: molecular mechanisms and therapeutic strategies

“…The most important inflammatory factor that stimulates neovascularization and causes vascular leakage is VEGF. 209 Hypoxia-inducible factor-1α is activated under hyperglycemic and hypoxic conditions, which leads to increased secretion of VEGF, and overexpressed VEGF, in turn promotes neovascularization through activation of the PI3K/Akt, 237 – 239 PKC, 240 , 241 and NF-κB 242 , 243 signal pathways. The expression of ICAM and nitric oxide synthase induced by VEGF promotes leukocyte adhesion and causes changes in vascular permeability and pathological neovascularization.…”

The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration

“…An additional up-stream player in the regulation of VEGF expression is the PKCβII/ELAV (Embryonic Lethal Abnormal Vision) cascade [ 207 , 208 , 209 ]. ELAV are a small family of proteins, which includes the ubiquitously expressed ELAVL1 (also known as HuA and HuR) and the neuron-specific members neuronal ELAV (nELAV, namely HuB, HuC and HuD).…”

Troxerutin suppress inflammation response and oxidative stress in jellyfish dermatitis by activating Nrf2/HO-1 signaling pathway

“…The pathological results demonstrated a significant reduction in the level of inflammation and elimination of edema. In addition, the cell survival rate can be improved by TRX, which has no harmful effects in vitro ( 42 ) and effectively suppresses the levels of pro-inflammatory cytokines. Furthermore, intercellular ROS accumulation in TE cells was reduced by TRX treatment.…”