Abstract
Mitochondrial diseases (MD) are heterogeneous disorders because of impairment of respiratory chain function leading to oxidative stress. We hypothesized that in MD the vascular endothelium may be affected by increased oxidative/nitrative stress causing a reduction of nitric oxide availability. We therefore, investigated the pathobiology of vasculature in MD patients by assaying the presence of 3-nitrotyrosine in muscle biopsies followed by the proteomic identification of proteins which undergo tyrosine nitration. We then measured the flow-mediated vasodilatation as a proof of altered nitric oxide generation/bioactivity. Here, we show that 3-nitrotyrosine staining is specifically located in the small vessels of muscle tissue and that the reaction is stronger and more evident in a significant percentage of vessels from MD patients as compared with controls. Eleven specific proteins which are nitrated under pathological conditions were identified; most of them are involved in energy metabolism and are located mainly in mitochondria. In MD patients the flow-mediated vasodilatation was reduced whereas baseline arterial diameters, blood flow velocity and endothelium-independent vasodilatation were similar to controls. The present results provide evidence that in MD the vessel wall is a target of increased oxidative/nitrative stress.
Highlights
From the ‡Department of Neurological Sciences and Vision, Section of Clinical Neurology, University of Verona, Italy, §Department of Chemistry, Indiana University, Bloomington, Indiana, 47405, ¶Department of Biomedical and Surgical Sciences, Section of Internal Medicine, University of Verona, Italy, and ʈDepartment of Medicine and Public Health, Section of Pharmacology, University of Verona, Verona, Italy
We investigated the pathobiology of vasculature in Mitochondrial diseases (MD) first, by assaying the presence of 3-NT in muscle biopsies followed by the proteomic identification of proteins that undergo tyrosine nitration, and by measuring the flowmediated vasodilatation (FMD) as a proof of altered nitric oxide (NO) generation/bioactivity
Immunohistochemistry and Confocal Fluorescence Microscopy—Nitrotyrosine was detected in the wall of small blood vessels, which were located within the interfascicular septa, from the patients’ muscle biopsy whereas no staining was observed in the examined capillaries (Fig. 1)
Summary
F a Mitochondrial myopathy and diabetes mellitus. A hallmark of these nitrogen species is the conversion of tyrosine to 3-nitrotyrosine (3-NT), whether free or part of a polypeptide chain [11, 12]. This nitration of tyrosine can compromise the functional and/or structural integrity of target proteins [13,14,15]. We investigated the pathobiology of vasculature in MD first, by assaying the presence of 3-NT in muscle biopsies followed by the proteomic identification of proteins that undergo tyrosine nitration, and by measuring the flowmediated vasodilatation (FMD) as a proof of altered NO generation/bioactivity
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.