Bradykinin protects against oxidative stress-induced endothelial cell senescence.
Premature aging (senescence) of endothelial cells might play an important role in the development and progression of hypertension and atherosclerosis. We hypothesized that bradykinin, a hormone that mediates vasoprotective effects of angiotensin-converting enzyme inhibitors, protects endothelial cells from oxidative stress-induced senescence. Bradykinin treatment (0.001 to 1 nmol/L) dose-dependently decreased senescence induced by 25 micromol/L of H(2)O(2) in cultured bovine aortic endothelial cells, as witnessed by a complete inhibition of increased senescent cell numbers and a 34% reduction of the levels of the senescence-associated cell cycle protein p21. Because H(2)O(2) induces senescence through superoxide-induced DNA damage, single-cell DNA damage was measured by comet assay. Bradykinin reduced DNA damage to control levels. The protective effect of bradykinin also resulted in a significant increase in the migration of H(2)O(2)-treated bovine aorta endothelial cells in an in vitro endothelial injury model, or "scratch" assay. The protective effect of bradykinin was abolished by the bradykinin B2 receptor antagonist HOE-140 and the NO production inhibitor N(omega)-methyl-L-arginine acetate salt. Therefore, we conclude that bradykinin protects endothelial cells from superoxide-induced senescence through bradykinin B2 receptor- and NO-mediated inhibition of DNA damage.
Oeseburg
Hisko
H
Department of Experimental Cardiology, AB 43, University Medical Center Groningen, Antonius Deusinglaan 1, Building 3211, 9713 AV Groningen, The Netherlands. h.oeseburg@thorax.umcg.nl
Iusuf
Dilek
D
van der Harst
Pim
P
van Gilst
Wiek H
WH
Henning
Robert H
RH
Roks
Anton J M
AJ
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology*; D065094:Bradykinin B2 Receptor Antagonists; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; D043782:Receptor, Bradykinin B2; D014665:Vasodilator Agents; D009569:Nitric Oxide; C065679:icatibant; D001920:Bradykinin