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(Hypertension. 2009;53:417.)
© 2009 American Heart Association, Inc.

Original Articles Part 2

Bradykinin Protects Against Oxidative Stress–Induced Endothelial Cell Senescence

Hisko Oeseburg; Dilek Iusuf; Pim van der Harst; Wiek H. van Gilst; Robert H. Henning; Anton J.M. Roks

From the Departments of Experimental Cardiology (H.O., P.v.d.H., W.H.v.G.) and Clinical Pharmacology (D.I., R.H.H.), University Medical Center Groningen, Groningen, The Netherlands; and the Division of Pharmacology, Vascular and Metabolic Disease (A.J.M.R.), Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Correspondence to Hisko Oeseburg, Department of Experimental Cardiology, AB 43, University Medical Center Groningen, Antonius Deusinglaan 1, Building 3211, 9713 AV Groningen, The Netherlands. E-mail h.oeseburg{at}thorax.umcg.nl

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 µmol/L of H₂O₂ 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 H₂O₂ 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 H₂O₂-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-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.

Key Words: senescence • endothelial • bradykinin • reactive oxygen species • DNA damage