title: Adrenergic DNA damage of embryonic pluripotent cells via β2 receptor signalling.
abstract: Embryonic pluripotent cells are sensitive to genotoxicity though they need more stringent genome integrity to avoid compromising multiple cell lineages and subsequent generations. However it remains unknown whether the cells are susceptible to adrenergic stress which can induce somatic cell genome lesion. We have revealed that adrenergic stress mediators cause DNA damage of the cells through the β2 adrenergic receptor/adenylate cyclase/cAMP/PKA signalling pathway involving an induction of intracellular reactive oxygen species (ROS) accumulation. The adrenergic stress agonists adrenaline, noradrenaline, and isoprenaline caused DNA damage and apoptosis of embryonic stem (ES) cells and embryonal carcinoma stem cells. The effects were mimicked by β2 receptor-coupled signalling molecules and abrogated by selective blockade of β2 receptors and inhibition of the receptor signalling pathway. RNA interference targeting β2 receptors of ES cells conferred the cells the ability to resist the DNA damage and apoptosis. In addition, adrenergic stimulation caused a consistent accumulation of ROS in the cells and the effect was abrogated by β2 receptor blockade; quenching of ROS reversed the induced DNA damage. This finding will improve the understanding of the stem cell regulatory physiology/pathophysiology in an adrenergic receptor subtype signalling mechanism.
authors.affiliation: Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Department of Pharmacy, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Xu-Ping
authors.initials: XP
authors.lastname: Ding
authors.affiliation: Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China.
authors.forename: Shi-Min
authors.initials: SM
authors.lastname: An
authors.affiliation: Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China.
authors.forename: Ya-Bin
authors.initials: YB
authors.lastname: Tang
authors.affiliation: Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Xin-Jie
authors.initials: XJ
authors.lastname: Yang
authors.affiliation: Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges University, Hubei 443003, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Teng
authors.affiliation: Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Department of Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China.
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D053595:Embryonic Stem Cells; D004837:Epinephrine / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D009638:Norepinephrine / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D006657:Histones; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018343:Receptors, Adrenergic, beta-2; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D009638:Norepinephrine; D004837:Epinephrine