NecroX-7 prevents oxidative stress-induced cardiomyopathy by inhibition of NADPH oxidase activity in rats.
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(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.
LG Life Sciences Ltd., R&D Park, Daejeon, 305-380, Republic of Korea.
Joonghoon
J
Park
Eok
E
Park
Bong-Hyun
BH
Ahn
Hyoung Jin
HJ
Kim
Ji-hoon
JH
Park
Sun Young
SY
Koo
Hyo-Shin
HS
Kwak
Heui Sul
HS
Park
Dong Wook
DW
Kim
Myoungsub
M
Song
Hyeon Joo
HJ
Yim
Dong Ook
DO
Seo
Soon Ha
SH
Kim
D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002460:Cell Line; D003402:Creatine Kinase / Q000097:blood; D004317:Doxorubicin / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D046228:Microarray Analysis; D032383:Myocytes, Cardiac / Q000187:drug effects; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D009930:Organic Chemicals / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020122:tert-Butylhydroperoxide / Q000037:antagonists & inhibitors
D002316:Cardiotonic Agents; D016166:Free Radical Scavengers; D009930:Organic Chemicals; C556282:necrox-7; D004317:Doxorubicin; D020122:tert-Butylhydroperoxide; D007770:L-Lactate Dehydrogenase; D019255:NADPH Oxidases; D003402:Creatine Kinase