title: Expression of CYP2E1 increases oxidative stress and induces apoptosis of cardiomyocytes in transgenic mice.
abstract: Cytochrome P450 2E1 (CYP2E1) is an effective generator of reactive oxygen species. Marked expression of CYP2E1 occurs in the heart and it is known to be regulated in the course of progression of myocardial ischemia and cardiomyopathy. We provide evidence that the expression of CYP2E1 is strongly up-regulated in cTnT(R141W) transgenic mice with dilated cardiomyopathy. Heart tissue-specific CYP2E1 transgenic mice were produced to study the effects of CYP2E1 overexpression on the heart. Increased mortality, chamber dilation and contractile dysfunction, as well as myocyte disarray, interstitial fibrosis, ultrastructural degeneration with myofibrillar disorganization and mitochondria damage, were observed in CYP2E1 transgenic mice and cTnT(R141W) transgenic mice. In addition, levels of H(2) O(2) and malondialdehyde were increased and levels of glutathione and total antioxidant capability were strongly reduced in CYP2E1 transgenic mice and cTnT(R141W) transgenic mice. Myocyte apoptosis was significantly increased by 19-fold in CYP2E1 transgenic mice and by 11-fold in cTnT(R141W) transgenic mice, respectively, compared to wild-type mice. Mitochondrial-dependent apoptotic signal transduction events, such as cytochrome c release from mitochondria into the cytosol and the expression of cleaved (active) caspases 3 and 9, were significantly increased in CYP2E1 transgenic mice and cTnT(R141W) transgenic mice. These results demonstrate that CYP2E1 over-expression produces apoptosis and that the up-regulation of CYP2E1 in cTnT(R141W) transgenic mice also correlates with apoptosis in this model.
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.forename: Wei
authors.initials: W
authors.lastname: Dong
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiongzhi
authors.initials: X
authors.lastname: Quan
authors.forename: Chunmei
authors.initials: C
authors.lastname: Ma
authors.forename: Hong
authors.initials: H
authors.lastname: Lian
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress
chemical_list: D019392:Cytochrome P-450 CYP2E1