THE NADPH OXIDASE NOX4 RESTRICTS THE REPLICATIVE LIFESPAN OF HUMAN ENDOTHELIAL CELLS
Résumé
The free radical theory of ageing proposes that reactive oxygen species (ROS) are major driving forces of ageing, and are also critically involved in cellular senescence. Besides the mitochondrial respiratory chain, alternative sources of ROS have been described, which might contribute to cellular senescence. NADPH oxidases are well-known sources of superoxide, which contribute to the antimicrobial capabilities of macrophages, a process involving the prototypical member of the family referred to as Nox2. However, in the recent years non-phagocytic homologues of Nox2 have been identified, which are involved in processes other than the host defence. Superoxide anions produced by these enzymes are believed to play a major role in signalling by MAP kinases and stress-activated kinases, but could also contribute to cellular senescence, which is known to involve oxygen radicals. In human umbilical vein endothelial cells (HUVEC), Nox4 is predominantly expressed, but its role for replicative senescence of HUVEC remains to be elucidated. Using shRNA-mediated knockdown of Nox4, implicating lentiviral vectors, we addressed the question if lifelong depletion of Nox4 in HUVEC would influence the senescent phenotype. We found a significant extension of the replicative lifespan of HUVEC upon knockdown of Nox4. Surprisingly, mean telomere length was significantly reduced in Nox4-depleted cells. Nox4 depletion had no discernable influence on the activity of MAP kinases and stress-activated kinases, but reduced the degree of oxidative DNA damage. These data suggest that Nox4 activity increases oxidative damage in HUVEC leading to loss of replicative potential which is at least partly independent of telomere attrition.
Origine : Fichiers produits par l'(les) auteur(s)
Loading...