title: A role for mitochondrial oxidants in stress-induced premature senescence of human vascular smooth muscle cells.
abstract: Mitochondria are a major source of cellular oxidants and have been implicated in aging and associated pathologies, notably cardiovascular diseases. Vascular cell senescence is observed in experimental and human cardiovascular pathologies. Our previous data highlighted a role for angiotensin II in the induction of telomere-dependent and -independent premature senescence of human vascular smooth muscle cells and suggested this was due to production of superoxide by NADPH oxidase. However, since a role for mitochondrial oxidants was not ruled out we hypothesise that angiotensin II mediates senescence by mitochondrial superoxide generation and suggest that inhibition of superoxide may prevent vascular smooth muscle cell aging in vitro. Cellular senescence was induced using a stress-induced premature senescence protocol consisting of three successive once-daily exposure of cells to 1×10(-8) mol/L angiotensin II and was dependent upon the type-1 angiotensin II receptor. Angiotensin stimulated NADPH-dependent superoxide production as estimated using lucigenin chemiluminescence in cell lysates and this was attenuated by the mitochondrial electron transport chain inhibitor, rotenone. Angiotensin also resulted in an increase in mitoSOX fluorescence indicating stimulation of mitochondrial superoxide. Significantly, the induction of senescence by angiotensin II was abrogated by rotenone and by the mitochondria-targeted superoxide dismutase mimetic, mitoTEMPO. These data suggest that mitochondrial superoxide is necessary for the induction of stress-induced premature senescence by angiotensin II and taken together with other data suggest that mitochondrial cross-talk with NADPH oxidases, via as yet unidentified signalling pathways, is likely to play a key role.
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK.
authors.forename: Yogita
authors.initials: Y
authors.lastname: Mistry
authors.forename: Toryn
authors.initials: T
authors.lastname: Poolman
authors.forename: Bryan
authors.initials: B
authors.lastname: Williams
authors.forename: Karl E
authors.initials: KE
authors.lastname: Herbert
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D011945:Receptors, Angiotensin / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*
chemical_list: D011945:Receptors, Angiotensin; D012402:Rotenone; D013481:Superoxides; D000804:Angiotensin II; D019255:NADPH Oxidases
keywords: Angiotensin II; Cell senescence; Mitochondria; Stress-induced premature senescence; Superoxide; Vascular smooth muscle cell