Protective mechanisms of NO preconditioning against NO-induced apoptosis in H9c2 cells: role of PKC and COX-2.
Cardiomyocyte apoptosis is involved in several cardiovascular diseases, including ischemia, hypertrophy and heart failure. Nitric oxide (NO) signalling is crucial in the regulation of cardiomyocyte apoptosis, capable of both inducing and preventing apoptosis depending upon the level of NO production. Growing evidence suggests that NO preconditioning has cardioprotective effects, but the mechanism remains unclear. The purpose of this study was to elucidate how NO preconditioning inhibits subsequent NO-induced apoptosis in H9c2 cells. According to the data, preconditioning with a low concentration of sodium nitroprusside (SNP, 0.3 mM) inhibited subsequent high-concentration-SNP (1.5 mM)-induced apoptosis and this effect was reversed by the protein kinase C (PKC) inhibitor chelerythrine and the cyclooxygenase-2 (COX-2) inhibitor rofecoxib. Low-concentration-SNP-mediated protection involved extracellular signal regulated kinase 1/2 (ERK1/2), a signal transducers and activators of transcription 1/3 (STAT1/3) activation and increased COX-2 expression. Activation of ERK1/2 and STAT1/3 was abolished by chelerythrine. However, COX-2 expression was not inhibited, implying that the COX-2-mediated protective effect occurred via a PKC-independent pathway. The results showed that low-concentration-SNP preconditioning suppresses subsequent high-concentration-SNP-induced apoptosis by ERK1/2-STAT 1/3 activation via PKC-dependent mechanisms in H9c2 cells. COX-2 also plays a role in NO-induced preconditioning, but is independent of PKC.
Kwak
Hyun-Jeong
HJ
Division of Cardiovascular Diseases, Center for Biomedical Sciences, National Institutes of Health, Eunpyung-gu, Seoul, Korea.
Park
Kyoung Mi
KM
Choi
Hye-Eun
HE
Park
Hyun-Young
HY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053119:Benzophenanthridines / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line / Q000166:cytology / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000502:physiology*; D005318:Fetal Heart / Q000166:cytology; D019157:Ischemic Preconditioning, Myocardial; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000633:toxicity*; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D026423:S-Nitroso-N-Acetylpenicillamine / Q000008:administration & dosage / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D053119:Benzophenanthridines; D002316:Cardiotonic Agents; D020030:Nitric Oxide Donors; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; C016299:chelerythrine; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3