期刊
MOLECULAR AND CELLULAR ENDOCRINOLOGY
卷 392, 期 1-2, 页码 14-22出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2014.05.010
关键词
6014; PARP-1; Cardiac hypertrophy; NAD; SIRT6
资金
- National Natural Science Foundation of China [81072641, 81273499, 81200096]
- National Science and Technology Major Project of China Key New Drug Creation and Manufacturing Program [2011ZX09401-307]
- Natural Science Foundation of Guangdong Province [S2011030003190]
- Major Project of Guangdong Province [2008A030201013, 2012A080201007]
- Major Project of Department of Education of Guangdong Province [CXZD1006]
- Major Project of Guangzhou City [2011Y1-00017]
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 of cellular NAD and SIRT6 deacetylase activity induced by Ana 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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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