title: Bradykinin inhibits oxidative stress-induced senescence of endothelial progenitor cells through the B2R/AKT/RB and B2R/EGFR/RB signal pathways.
abstract: Circulating endothelial progenitor cells (EPCs) have multiple protective effects that facilitate repair of damage to tissues and organs. However, while various stressors are known to impair EPC function, the mechanisms of oxidative stress-induced EPC senescence remains unknown. We demonstrated that B2 receptor (B2R) expression on circulating CD34(+) cells was significantly reduced in patients with diabetes mellitus (DM) as compared to healthy controls. Furthermore, CD34(+) cell B2R expression in patients with DM was inversely correlated with plasma myeloperoxidase concentrations. Bradykinin (BK) treatment decreased human EPC (hEPC) senescence and intracellular oxygen radical production, resulting in reduced retinoblastoma 1 (RB) RNA expression in H2O2-induced senescent hEPCs and a reversal of the B2R downregulation that is normally observed in senescent cells. Furthermore, BK treatment of H2O2-exposed cells leads to elevated phosphorylation of RB, AKT, and cyclin D1 compared with H2O2-treatment alone. Antagonists of B2R, PI3K, and EGFR signaling pathways and B2R siRNA blocked BK protective effects. In summary, this study demonstrates that BK significantly inhibits oxidative stress-induced hEPC senescence though B2R-mediated activation of PI3K and EGFR signaling pathways.
authors.affiliation: Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Fu
authors.affiliation: Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, China.
authors.forename: Yuning
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, China.
authors.forename: Genshan
authors.initials: G
authors.lastname: Ma
authors.affiliation: Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, China.
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Yao
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology*; D065094:Bradykinin B2 Receptor Antagonists / Q000494:pharmacology; D016022:Case-Control Studies; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D019610:Cytoprotection; D003920:Diabetes Mellitus / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D066026:Endothelial Progenitor Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D043782:Receptor, Bradykinin B2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D018952:Antigens, CD34; D000975:Antioxidants; D065094:Bradykinin B2 Receptor Antagonists; D016877:Oxidants; D047428:Protein Kinase Inhibitors; D043782:Receptor, Bradykinin B2; D016160:Retinoblastoma Protein; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D001920:Bradykinin
keywords: B2 receptor; Gerotarget; bradykinin; endothelial progenitor cells; senescence