title: Accumulation of cytochrome P450 induced by proteasome inhibition during cardiac ischemia.
abstract: Increasing evidence shows that cytochrome P450 (CYP) contributes to cardiac reperfusion injury. However, there have been few reports about the roles of CYPs in cardiac ischemia. The aim of the present study was to investigate the CYP expression and activity during ischemia using an in vivo rat model of myocardial infarction. Cardiac ischemia was evoked by ligation of the left anterior descending coronary artery for 1 h. The protein levels of CYP 2C6, 2E1 and 2J3 increased in the ischemic region of the rat hearts, while the mRNA levels of CYPs were unchanged. CYP 2C6 activity was significantly elevated in the ischemic region, and the activities of 2E1 and 2J3 tended to increase during ischemia. The proteasome activity decreased and the expression of ubiquitinated proteins increased in the ischemic region. Remarkably, ubiquitinated CYP 2C6, 2E1 and 2J3 were detected in the ischemic area, suggesting that CYP proteins accumulate in the ischemic region as a result of the suppression of their degradation due to the reduction of proteasome activity. The amounts of reactive oxygen species and protein carbonyls increased, and proteasome subunits, Rpt3 and Rpt5, were carbonylated in the ischemic region of the hearts, indicating that the proteasome is oxidized during ischemia. Taken together, our findings indicate that CYPs, especially CYP 2C6, were accumulated by oxidative impairment of the proteasome in the ischemic region of rat hearts. Accumulated CYPs might be involved in myocardial infarction and dysfunction during reperfusion.
authors.affiliation: Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan. ishiyasu@hiroshima-u.ac.jp
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ishihara
authors.forename: Ai
authors.initials: A
authors.lastname: Hamaguchi
authors.forename: Masaya
authors.initials: M
authors.lastname: Sekine
authors.forename: Ayumi
authors.initials: A
authors.lastname: Hirakawa
authors.forename: Norio
authors.initials: N
authors.lastname: Shimamoto
mesh_terms: D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology* / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D017382:Reactive Oxygen Species; D025801:Ubiquitin; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; C089877:Cyp2c6v1 protein, rat; C106098:Cyp2j3 protein, rat; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase; D046988:Proteasome Endopeptidase Complex