NecroX-5 suppresses sodium nitroprusside-induced cardiac cell death through inhibition of JNK and caspase-3 activation.
Although sodium nitroprusside (SNP) is an effective hypotensive drug and is often used in pediatric intensive care units and to treat acute heart failure, clinical application of SNP is limited by its cardiotoxicity. NecroX-5 (NX-5) was recently developed and has the capacity to inhibit necrotic cell death. No current literature addresses whether NX-5 suppresses SNP-induced cell death or its mechanism of action. We have investigated the protective role of NX-5 against SNP-induced cell death in cardiomyocyte-like H9c2 cells. SNP treatment induced severe cell death, possibly through phosphorylation of stress-activated protein kinase/c-Jun NH₂-terminal kinase (JNK) and activation of the apoptotic signaling pathway, including downregulation of Bcl-2 and cleavage of caspase-3. However, NX-5 suppresses SNP-induced cell death through inhibition of JNK activation and suppression of both downregulation of Bcl-2 protein expression and caspase-3 cleavage. These findings will provide insights and facilitate development of antidotes to SNP toxicity in cardiac cells.
National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, 633-165 Gaegeum-dong Busanjin-gu, Busan, 614 735, Republic of Korea.
Sung Ryul
SR
Lee
Seon Joong
SJ
Lee
Soon Ha
SH
Kim
Kyung Soo
KS
Ko
Byoung Doo
BD
Rhee
Zhelong
Z
Xu
Nari
N
Kim
Jin
J
Han
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D066126:Cardiotoxicity / Q000188:drug therapy / Q000517:prevention & control; D053148:Caspase 3 / Q000096:biosynthesis / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology*; D002460:Cell Line; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009206:Myocardium / Q000166:cytology; D009569:Nitric Oxide / Q000096:biosynthesis; D009599:Nitroprusside / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D013450:Sulfones / Q000494:pharmacology*
D061945:Caspase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; C574766:NecroX-5; D019253:Proto-Oncogene Proteins c-bcl-2; D013450:Sulfones; D009599:Nitroprusside; D009569:Nitric Oxide; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3
cell death; heart/lung/blood vessels; skeletal/cardiac muscle