Sulodexide Prevents Hyperglycemia-Induced Endothelial Dysfunction and Oxidative Stress in Porcine Retinal Arterioles
Alice Dauth,
Andrzej Bręborowicz,
Yue Ruan,
Qi Tang,
Jenia K. Zadeh,
Elsa W. Böhm,
Norbert Pfeiffer,
Pratik H. Khedkar,
Andreas Patzak,
Ksenija Vujacic-Mirski,
Andreas Daiber,
Adrian Gericke
Affiliations
Alice Dauth
Department of Neurosurgery, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
Andrzej Bręborowicz
Department of Pathophysiology, Poznań University of Medical Sciences, 60-512 Poznań, Poland
Yue Ruan
Department of Ophthalmology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
Qi Tang
Department of Ophthalmology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
Jenia K. Zadeh
Department of Ophthalmology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
Elsa W. Böhm
Department of Ophthalmology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
Norbert Pfeiffer
Department of Ophthalmology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
Pratik H. Khedkar
Institute of Translational Physiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
Andreas Patzak
Institute of Translational Physiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
Ksenija Vujacic-Mirski
Department of Cardiology, Cardiology 1, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
Andreas Daiber
Department of Cardiology, Cardiology 1, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
Adrian Gericke
Department of Ophthalmology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany
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 videomicroscopy. Reactive oxygen species (ROS) were quantified by dihydroethidium (DHE) fluorescence. Using high-pressure liquid chromatography (HPLC), the intrinsic antioxidant properties of sulodexide 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 oxidative stress and endothelial dysfunction in porcine retinal arterioles, possibly by modulation of redox enzyme expression.
