Metformin suppresses high glucose-induced poly(adenosine diphosphate-ribose) polymerase overactivation in aortic endothelial cells
| Autor: | Nicolas Marie, Jean-Louis Beaudeux, Meriem Mahrouf-Yorgov, J. Peynet, Raja Djelidi, Alain Legrand, Didier Borderie, Dominique Bonnefont-Rousselot |
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| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Endocrinology Diabetes and Metabolism Poly ADP ribose polymerase Blotting Western Fluorescent Antibody Technique Biology Poly(ADP-ribose) Polymerase Inhibitors Poly (ADP-Ribose) Polymerase Inhibitor chemistry.chemical_compound Endocrinology Internal medicine medicine Animals Hypoglycemic Agents Calphostin Cells Cultured Kinase Adenosine Metformin Enzyme Activation Glucose chemistry Cattle NAD+ kinase Endothelium Vascular Poly(ADP-ribose) Polymerases Peroxynitrite Nicotinamide adenine dinucleotide phosphate medicine.drug |
| Zdroj: | Metabolism: clinical and experimental. 58(4) |
| ISSN: | 1532-8600 |
| Popis: | Overactivation of poly(adenosine diphosphate-ribose) polymerase (PARP), an enzyme involved in cellular response to DNA injury resulting from oxidative and nitrosative stress, is considered to play a key role in the pathogenesis of diabetes complications by promoting numerous vascular dysfunctions. In this study, we examined the ability of metformin, which was reported to possess intrinsic vasculoprotective properties independently of its antihyperglycemic effects, to inhibit PARP activation induced by high glucose concentrations in bovine aortic endothelial cells; and we investigated the potential mechanisms involved in this inhibition. The PARP activity was measured by cellular enzyme-linked immuno-specific assay (CELISA) method; cell poly(ribosyl)ated protein polymer accumulation was evaluated by immunofluorescence. Peroxynitrite anion productions were determined using dihydrorhodamine 123 fluoroprobe; and expression of p47phox subunit of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase was analyzed by Western blot in the absence and presence of protein kinase C and NAD(P)H oxidase inhibitors (calphostin and diphenyleneiodonium chloride, respectively). Our data showed that a therapeutically relevant concentration of metformin (5.10(-5) mol/L) was able to abolish PARP activation, to reduce poly(ribosyl)ated protein polymer accumulation, to decrease intracellular peroxynitrite anion level, and to reverse the overexpression of p47phox in bovine aortic endothelial cells stimulated by 25 mmol/L glucose in a similar manner to that of calphostin or diphenyleneiodonium chloride. Taken together, these results suggest that metformin could inhibit glucose-induced PARP activation through blockade of a protein kinase C-dependent NAD(P)H oxidase activation pathway. We propose that some of the beneficial effects of metformin on vascular endothelial cell functions in diabetes may be related to its inhibitory effect on PARP overactivation and its deleterious consequences. |
| Databáze: | OpenAIRE |
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