title: AG-690/11026014, a novel PARP-1 inhibitor, protects cardiomyocytes from AngII-induced hypertrophy.
abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) enzyme, as a sensor of DNA damage, could convert nicotinamide adenine dinucleotide (NAD) into long poly(ADP-ribose) chains and regulate many cellular processes, including DNA repair, gene transcription, cell survival and chromatin remodeling. However, excessive activation of PARP-1 depletes its substrate NAD and leads to cell death. Mounting evidences have shown that PARP-1 overactivation plays a pivotal role in the pathogenesis of cardiac hypertrophy and heart failure. In present study, a novel PARP-1 inhibitor AG-690/11026014 (6014) was identified based on virtual screening and validated by bioassay. Our results further showed that 6014 prevented the cardiomyocytes from AngII-induced hypertrophy, accompanying attenuation of the mRNA and protein expressions of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP), and reduce in the cell surface area. Additionally, 6014 reversed the depletion ofcellular NAD and SIRT6 deacetylase activity induced by AngII in cardiomyocytes. These observations suggest that anti-hypertrophic effect of 6014 might be partially attributed to the rescue of NAD depletion and subsequent restoring of SIRT6 activity by inhibition of PARP-1. Moreover, 6014 attenuated the generation of oxidative stress via suppression of NADPH oxidase 2 and 4, which might probably contribute to the inhibition of PARP-1.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Guo-Wen
authors.initials: GW
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Zhuo-Ming
authors.initials: ZM
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Lu-Ping
authors.initials: LP
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China. Electronic address: yejt@mail.sysu.edu.cn.
authors.forename: Jian-Tao
authors.initials: JT
authors.lastname: Ye
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China. Electronic address: luohb77@mail.sysu.edu.cn.
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China. Electronic address: liupq@mail.sysu.edu.cn.
authors.forename: Pei-Qing
authors.initials: PQ
authors.lastname: Liu
mesh_terms: D000804:Angiotensin II; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019610:Cytoprotection / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008562:Membrane Glycoproteins / Q000378:metabolism; D062105:Molecular Docking Simulation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D009243:NAD / Q000378:metabolism; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D037761:Sirtuins / Q000378:metabolism; D013864:Thioglycolates / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D014970:Xanthines / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000595233:AG-690; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D013864:Thioglycolates; D014970:Xanthines; D009243:NAD; D000804:Angiotensin II; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D011065:Poly(ADP-ribose) Polymerases; D037761:Sirtuins; C560607:sirtuin 6, rat
keywords: 6014; Cardiac hypertrophy; NAD; PARP-1; SIRT6