Sulodexide prevents hyperglycemia-induced endothelial dysfunction and oxidative stress in porcine retinal arterioles
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Abstract
Diabetes mellitus may cause severe damage to retinal blood vessels. The central aim
of this study was to test the hypothesis that sulodexide, a mixture of glycosaminoglycans, has a
protective effect against hyperglycemia-induced endothelial dysfunction in the retina. Functional
studies were performed in isolated porcine retinal arterioles. Vessels were cannulated and incubated
with highly concentrated glucose solution (HG, 25 mM D-glucose) +/− sulodexide (50/5/0.5 µg/mL)
or normally concentrated glucose solution (NG, 5.5 mM D-glucose) +/− sulodexide for two hours.
Endothelium-dependent and endothelium-independent vasodilatation were measured by videomi croscopy. Reactive oxygen species (ROS) were quantified by dihydroethidium (DHE) fluorescence.
Using high-pressure liquid chromatography (HPLC), the intrinsic antioxidant properties of sulodex ide were investigated. Quantitative PCR was used to determine mRNA expression of regulatory,
inflammatory, and redox genes in retinal arterioles, some of which were subsequently quantified at
the protein level by immunofluorescence microscopy. Incubation of retinal arterioles with HG caused
significant impairment of endothelium-dependent vasodilation, whereas endothelium-independent
responses were not affected. In the HG group, ROS formation was markedly increased in the vascular
wall. Strikingly, sulodexide had a protective effect against hyperglycemia-induced ROS formation in
the vascular wall and had a concentration-dependent protective effect against endothelial dysfunction.
Although sulodexide itself had only negligible antioxidant properties, it prevented hyperglycemia induced overexpression of the pro-oxidant redox enzymes, NOX4 and NOX5. The data of the present
study provide evidence that sulodexide has a protective effect against hyperglycemia-induced oxida tive stress and endothelial dysfunction in porcine retinal arterioles, possibly by modulation of redox
enzyme expression.