Glutathione Peroxidase-1-Deficiency Enhances Age-Dependent Vascular Dysfunction

Goal We investigate, whether glutathione peroxidase (GPx‐1) deficiency enhances ageing‐dependent vascular dysfunction and the formation of reactive oxygen and nitrogen species (RONS). Methods 2, 6 and 12 months old mice were used. Vascular function was assessed via isometric tension studies. RONS were assessed by optical, immunohistochemical and immunoblotting‐based techniques. Function of endothelial NO synthase (eNOS) was assessed by phosphorylation and S‐glutathionylation pattern. Results GPx‐1 −/− ‐mice had significantly impaired vascular function, compared to wild type‐mice. RONS in mitochondria, heart‐tissue and serum was enhanced with increased age, but not significantly different compared to wild type‐mice. eNOS dysfunction due to S‐gluthationylation and phosphorylation at Thr495 and Tyr657 was increased in GPx‐1 −/− ‐mice. Conclusion GPx‐1 −/− ‐mice were expected to display a higher level of H 2 O 2 . However, we could only detect minor differences between RONS in GPx‐1 −/− ‐mice and wild type‐mice, which could not explain the differences observed for vascular function with increasing age. The dramatic endothelial dysfunction in old GPx‐1 −/− ‐mice may be due to phosphorylation and S‐glutathionylation dependent inactivation/uncoupling of eNOS. Further investigations will focus on the expression of other antioxidant proteins and the role of GPx‐1 for vascular inflammation.