title: Cytochrome P450 omega-hydroxylase inhibition reduces cardiomyocyte apoptosis via activation of ERK1/2 signaling in rat myocardial ischemia-reperfusion.
abstract: Cytochrome P450 (CYP) omega-hydroxylases and their arachidonic acid metabolites play important roles in myocardial ischemia-reperfusion injury. In this study we investigated the effects of several selective CYP omega-hydroxylase inhibitors on myocardial ischemia/reperfusion-induced myocardial apoptosis. Rats were subjected 30 min of ischemia and 2 h of reperfusion. Groups received either 17-octadecynoic acid (17-ODYA, 0.3 or 3 mg/kg), N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS, 0.4 or 0.8 mg/kg), N-hydroxy-N'-(4-butyl-2-methylphenyl) formamidine (HET0016, 0.1 or 1 mg/kg) or vehicle 10 min prior to ischemia. To further assess the role of mitogen-activated protein kinases (MAPKs) in the CYP omega-hydroxylase inhibitor-induced anti-apoptotic effect, rats also received PD98059 (1 mg/kg), SB203580 (1 mg/kg) or SP600125 (6 mg/kg) 15 min prior to ischemia, with subsets of rats also receiving HET0016 10 min prior to ischemia. Compared with vehicle group, 17-ODYA, DDMS and HET0016 significantly inhibited myocardial apoptosis as evidenced by decreased DNA ladder formation, terminal dUTP deoxynucleotidyltransferase nick end-labeling (TUNEL) positive nuclear staining. They also decreased caspase-3 activity and Bax protein expression but up-regulated the expression of Bcl-2. Conversely, exogenous 20-HETE administration exerted opposite effects. Moreover, HET0016 increased the activity of extracellular signal-related protein kinases 1 and 2 (ERK1/2) but had no significant effect on p38 MAPK or c-Jun N-terminal kinase (JNK) during ischemia/reperfusion. Pretreatment with PD98059, the inhibitor of ERK1/2, but not SB203580 or SP600125, almost completely blocked the effect exerted by HET0016. Taken together, these data suggest that CYP omega-hydroxylase inhibition exerts significant anti-apoptosis effects, at least in part, by activation of ERK1/2 in ischemia/reperfusion heart.
authors.affiliation: Department of Pharmacology, School of Medicine, Wuhan University, Donghu Road, Wuhan, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Lv
authors.forename: Jing
authors.initials: J
authors.lastname: Wan
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Ao
authors.forename: Rengxiu
authors.initials: R
authors.lastname: Peng
mesh_terms: D000577:Amides / Q000494:pharmacology; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000577:Amides; D000578:Amidines; D005231:Fatty Acids, Unsaturated; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D013450:Sulfones; C047008:17-octadecynoic acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; C117975:DDMS; D042926:Cytochrome P-450 CYP4A; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3