NecroX-7 prevents oxidative stress-induced cardiomyopathy by inhibition of NADPH oxidase activity in rats

Park, Joonghoon; Park, Eok; Ahn, Bong-Hyun; Kim, Hyoung Jin; Park, Ji-hoon; Koo, Sun Young; Kwak, Hyo-Shin; Park, Heui Sul; Kim, Dong Wook; Song, Myoungsub; Yim, Hyeon Joo; Seo, Dong Ook

doi:10.1016/J.TAAP.2012.05.014

Title: NecroX-7 prevents oxidative stress-induced cardiomyopathy by inhibition of NADPH oxidase activity in rats

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Abstract

Oxidative stress is one of the causes of cardiomyopathy. In the present study, NecroXs, novel class of mitochondrial ROS/RNS scavengers, were evaluated for cardioprotection in in vitro and in vivo model, and the putative mechanism of the cardioprotection of NecroX-7 was investigated by global gene expression profiling and subsequent biochemical analysis. NecroX-7 prevented tert-butyl hydroperoxide (tBHP)-induced death of H9C2 rat cardiomyocytes at EC{sub 50} = 0.057 μM. In doxorubicin (DOX)-induced cardiomyopathy in rats, NecroX-7 significantly reduced the plasma levels of creatine kinase (CK-MB) and lactate dehydrogenase (LDH) which were increased by DOX treatment (p < 0.05). Microarray analysis revealed that 21 genes differentially expressed in tBHP-treated H9C2 cells were involved in ‘Production of reactive oxygen species’ (p = 0.022), and they were resolved by concurrent NecroX-7 treatment. Gene-to-gene networking also identified that NecroX-7 relieved cell death through Ncf1/p47phox and Rac2 modulation. In subsequent biochemical analysis, NecroX-7 inhibited NADPH oxidase (NOX) activity by 53.3% (p < 0.001). These findings demonstrate that NecroX-7, in part, provides substantial protection of cardiomyopathy induced by tBHP or DOX via NOX-mediated cell death. -- Highlights: ► NecroX-7 prevented tert-butyl hydroperoxide-induced in vitro cardiac cell death. ► NecroX-7 ameliorated doxorubicin-induced in vivo cardiomyopathy. ► NecroX-7 prevented oxidativemore »« less

Authors:

Park, Joonghoon; Park, Eok; Ahn, Bong-Hyun; Kim, Hyoung Jin ^[1]; Park, Ji-hoon ^[2]; Koo, Sun Young; Kwak, Hyo-Shin; Park, Heui Sul; Kim, Dong Wook; Song, Myoungsub; Yim, Hyeon Joo; Seo, Dong Ook ^[1]

LG Life Sciences Ltd., R and D Park, Daejeon, 305-380 (Korea, Republic of)
Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of)

Publication Date:: Wed Aug 15 00:00:00 EDT 2012

OSTI Identifier:: 22215874

Resource Type:: Journal Article

Journal Name:: Toxicology and Applied Pharmacology

Additional Journal Information:: Journal Volume: 263; Journal Issue: 1; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; APOPTOSIS; CREATINE; DOXORUBICIN; IN VITRO; IN VIVO; INHIBITION; LACTATE DEHYDROGENASE; MITOCHONDRIA; NECROSIS; OXIDASES; OXIDATION; RATS

Citation Formats


                    Park, Joonghoon, Park, Eok, Ahn, Bong-Hyun, Kim, Hyoung Jin, Park, Ji-hoon, Koo, Sun Young, Kwak, Hyo-Shin, Park, Heui Sul, Kim, Dong Wook, Song, Myoungsub, Yim, Hyeon Joo, Seo, Dong Ook, and Kim, Soon Ha, E-mail: shakim@lgls.com. NecroX-7 prevents oxidative stress-induced cardiomyopathy by inhibition of NADPH oxidase activity in rats.  United States: N. p., 2012. 
        Web.  doi:10.1016/J.TAAP.2012.05.014.

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                    Park, Joonghoon, Park, Eok, Ahn, Bong-Hyun, Kim, Hyoung Jin, Park, Ji-hoon, Koo, Sun Young, Kwak, Hyo-Shin, Park, Heui Sul, Kim, Dong Wook, Song, Myoungsub, Yim, Hyeon Joo, Seo, Dong Ook, & Kim, Soon Ha, E-mail: shakim@lgls.com. NecroX-7 prevents oxidative stress-induced cardiomyopathy by inhibition of NADPH oxidase activity in rats.  United States.  https://doi.org/10.1016/J.TAAP.2012.05.014

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                    Park, Joonghoon, Park, Eok, Ahn, Bong-Hyun, Kim, Hyoung Jin, Park, Ji-hoon, Koo, Sun Young, Kwak, Hyo-Shin, Park, Heui Sul, Kim, Dong Wook, Song, Myoungsub, Yim, Hyeon Joo, Seo, Dong Ook, and Kim, Soon Ha, E-mail: shakim@lgls.com. 2012.  
        "NecroX-7 prevents oxidative stress-induced cardiomyopathy by inhibition of NADPH oxidase activity in rats".  United States.  https://doi.org/10.1016/J.TAAP.2012.05.014.

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@article{osti_22215874,

  title        = {NecroX-7 prevents oxidative stress-induced cardiomyopathy by inhibition of NADPH oxidase activity in rats},

  author       = {Park, Joonghoon and Park, Eok and Ahn, Bong-Hyun and Kim, Hyoung Jin and Park, Ji-hoon and Koo, Sun Young and Kwak, Hyo-Shin and Park, Heui Sul and Kim, Dong Wook and Song, Myoungsub and Yim, Hyeon Joo and Seo, Dong Ook and Kim, Soon Ha, E-mail: shakim@lgls.com},

  abstractNote = {Oxidative stress is one of the causes of cardiomyopathy. In the present study, NecroXs, novel class of mitochondrial ROS/RNS scavengers, were evaluated for cardioprotection in in vitro and in vivo model, and the putative mechanism of the cardioprotection of NecroX-7 was investigated by global gene expression profiling and subsequent biochemical analysis. NecroX-7 prevented tert-butyl hydroperoxide (tBHP)-induced death of H9C2 rat cardiomyocytes at EC{sub 50} = 0.057 μM. In doxorubicin (DOX)-induced cardiomyopathy in rats, NecroX-7 significantly reduced the plasma levels of creatine kinase (CK-MB) and lactate dehydrogenase (LDH) which were increased by DOX treatment (p < 0.05). Microarray analysis revealed that 21 genes differentially expressed in tBHP-treated H9C2 cells were involved in ‘Production of reactive oxygen species’ (p = 0.022), and they were resolved by concurrent NecroX-7 treatment. Gene-to-gene networking also identified that NecroX-7 relieved cell death through Ncf1/p47phox and Rac2 modulation. In subsequent biochemical analysis, NecroX-7 inhibited NADPH oxidase (NOX) activity by 53.3% (p < 0.001). These findings demonstrate that NecroX-7, in part, provides substantial protection of cardiomyopathy induced by tBHP or DOX via NOX-mediated cell death. -- Highlights: ► NecroX-7 prevented tert-butyl hydroperoxide-induced in vitro cardiac cell death. ► NecroX-7 ameliorated doxorubicin-induced in vivo cardiomyopathy. ► NecroX-7 prevented oxidative stress and necrosis-enriched transcriptional changes. ► NecroX-7 effectively inhibited NADPH oxidase activation. ► Cardioprotection of Necro-7 was brought on by modulation of NADPH oxidase activity.},

  doi          = {10.1016/J.TAAP.2012.05.014},

  url          = {https://www.osti.gov/biblio/22215874},
  journal      = {Toxicology and Applied Pharmacology},

  issn         = {0041-008X},

  number       = 1,

  volume       = 263,

  place        = {United States},

  year         = {Wed Aug 15 00:00:00 EDT 2012},

  month        = {Wed Aug 15 00:00:00 EDT 2012}

}

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