title: Bradykinin inhibits oxidative stress-induced cardiomyocytes senescence via regulating redox state.
abstract: BACKGROUND
  Cell senescence is central to a large body of age related pathology, and accordingly, cardiomyocytes senescence is involved in many age related cardiovascular diseases. In consideration of that, delaying cardiomyocytes senescence is of great importance to control clinical cardiovascular diseases. Previous study indicated that bradykinin (BK) protected endothelial cells from senescence induced by oxidative stress. However, the effects of bradykinin on cardiomyocytes senescence remain to be elucidated. In this study, we investigated the effect of bradykinin on H2O2-induced H9C2 cells senescence.
  
  
  RESULTS
  Bradykinin pretreatment decreased the senescence induced by H2O2 in cultured H9C2 cells in a dose dependent manner. Interestingly, 1 nmol/L of BK almost completely inhibited the increase in senescent cell number and p21 expression induced by H2O2. Since H2O2 induces senescence through superoxide-induced DNA damage, we also observed the DNA damage by comet assay, and BK markedly reduced DNA damage induced by H2O2, and moreover, BK treatment significantly prevented reactive oxygen species (ROS) production in H9C2 cells treated with H2O2. Importantly, when co-incubated with bradykinin B2 receptor antagonist HOE-140 or eNOS inhibitor N-methyl-L-arginine acetate salt (L-NAME), the protective effects of bradykinin on H9C2 senescence were totally blocked. Furthermore, BK administration significantly prevented the increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity characterized by increased ROS generation and gp91 expression and increased translocation of p47 and p67 to the membrane and the decrease in superoxide dismutase (SOD) activity and expression induced by H2O2 in H9C2 cells, which was dependent on BK B2 receptor mediated nitric oxide (NO) release.
  
  
  CONCLUSIONS
  Bradykinin, acting through BK B2 receptor induced NO release, upregulated antioxidant Cu/Zn-SOD and Mn-SOD activity and expression while downregulating NADPH oxidase activity and subsequently inhibited ROS production, and finally protected against cardiomyocytes senescence induced by oxidative stress.
authors.affiliation: Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Ruolan
authors.initials: R
authors.lastname: Dong
authors.forename: Xizhen
authors.initials: X
authors.lastname: Xu
authors.forename: Geng
authors.initials: G
authors.lastname: Li
authors.forename: Wenjing
authors.initials: W
authors.lastname: Feng
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Junjie
authors.initials: J
authors.lastname: Zhao
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Tu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology*; D065094:Bradykinin B2 Receptor Antagonists; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects*; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000009:adverse effects; D005434:Flow Cytometry; D006861:Hydrogen Peroxide / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D065094:Bradykinin B2 Receptor Antagonists; D004791:Enzyme Inhibitors; D016877:Oxidants; D017382:Reactive Oxygen Species; D043782:Receptor, Bradykinin B2; D009569:Nitric Oxide; C065679:icatibant; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester