Inhibition of CYP2E1 attenuates chronic alcohol intake-induced myocardial contractile dysfunction and apoptosis.
Inhibition of CYP2E1 attenuates chronic alcohol intake-induced myocardial contractile dysfunction and apoptosis.
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CYP2E1 的抑制可减轻慢性酒精摄入引起的心肌收缩功能障碍和细胞凋亡。
DOI：
10.1016/j.bbadis.2012.08.014
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发表时间：
2013-01
影响因子：
6.2
通讯作者：
Ren, Jun
中科院分区：
文献类型：
--
作者：
Zhang, Rong-Huai;Gao, Jian-Yuan;Guo, Hai-Tao;Scott, Glenda I.;Eason, Anna R.;Wang, Xiao-Ming;Ren, Jun
酒精摄入与心肌收缩功能障碍和细胞凋亡有关，但其确切机制尚不清楚。本研究旨在检查细胞色素P450酶CYP 2 E1抑制对乙醇诱导的心功能不全的影响。成年雄性小鼠喂食4%乙醇液体或配对喂食对照饮食6周。在饮食喂养2周后，一组小鼠开始接受CYP 2 E1抑制剂二烯丙基硫醚（100 mg/kg/d，i. p.）在剩下的进食时间里使用超声心动图和IonOptix系统评估心脏功能。Western blot检测CYP 2 E1、血红素加氧酶-1（HO-1）、诱导型一氧化氮合酶（iNOS）、胞内钙调节蛋白肌浆网钙ATP酶、Na+-Ca 2+交换蛋白和受磷蛋白（phospholamban）、促凋亡蛋白半胱氨酸蛋白酶-3（caspase-3）、Bax、c-Jun-NH 2-末端激酶（JNK）和凋亡信号调节激酶-1（ASK-1）。乙醇导致CYP 2 E1、iNOS和受磷蛋白水平升高，HO-1和Na+-Ca 2+交换剂水平降低，心脏收缩和细胞内Ca 2+缺陷，心脏纤维化，明显的O2−产生和细胞凋亡伴随JNK和ASK-1磷酸化增加，二烯丙基硫醚显著减弱或消除这些作用。JNK和ASK-1的抑制剂而不是HO-1诱导剂或iNOS抑制剂消除了乙醇诱导的心肌细胞收缩功能障碍，证实了JNK和ASK-1信号传导在乙醇诱导的心肌损伤中的作用。综上所述，这些研究结果表明，通过CYP 2 E1的乙醇代谢可能有助于酒精性心肌病的发病机制，包括心肌收缩功能障碍，氧化应激和细胞凋亡，可能通过激活JNK和ASK-1信号。
Alcohol intake is associated with myocardial contractile dysfunction and apoptosis although the precise mechanism is unclear. This study was designed to examine the effect of the cytochrome P450 enzyme CYP2E1 inhibition on ethanol-induced cardiac dysfunction. Adult male mice were fed a 4% ethanol liquid or pair-fed control diet for 6 weeks. Following 2 weeks of diet feeding, a cohort of mice started to receive the CYP2E1 inhibitor diallyl sulfide (100 mg/kg/d, i.p.) for the remaining feeding duration. Cardiac function was assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate CYP2E1, heme oxygenase-1 (HO-1), iNOS, the intracellular Ca2+ regulatory proteins sarco(endo)plasmic reticulum Ca2+-ATPase, Na+-Ca2+ exchanger and phospholamban, pro-apoptotic protein cleaved caspase-3, Bax, c-Jun-NH2-terminal kinase (JNK) and apoptosis signal-regulating kinase (ASK-1). Ethanol led to elevated levels of CYP2E1, iNOS and phospholamban, decreased levels of HO-1 and Na+-Ca2+ exchanger, cardiac contractile and intracellular Ca2+ defects, cardiac fibrosis, overt O2− production, and apoptosis accompanied with increased phosphorylation of JNK and ASK-1, the effects were significantly attenuated or ablated by diallyl sulfide. Inhibitors of JNK and ASK-1 but not HO-1 inducer or iNOS inhibitor obliterated ethanol-induced cardiomyocyte contractile dysfunction, substantiating a role for JNK and ASK-1 signaling in ethanol-induced myocardial injury. Taken together, these findings suggest that ethanol metabolism through CYP2E1 may contribute to the pathogenesis of alcoholic cardiomyopathy including myocardial contractile dysfunction, oxidative stress and apoptosis, possibly through activation of JNK and ASK-1 signaling.
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DOI：
10.1152/ajpheart.00780.2001
发表时间：
2002-04-01
影响因子：
4.8
作者：
Duan, JH;McFadden, GE;Ren, J
通讯作者：
Ren, J
影响因子：
1.8
作者：
Cederbaum AI;Yang L;Wang X;Wu D
通讯作者：
Wu D
影响因子：
3.7
作者：
Guo R;Ren J
通讯作者：
Ren J
影响因子：
3
作者：
Maia Dantas, Aline;Ester Mohn, Claudia;Fernandez-Solari, Javier
通讯作者：
Fernandez-Solari, Javier
DOI：
10.1016/s1095-6433(02)00347-1
发表时间：
2003-03-01
影响因子：
2.3
作者：
Duan, JH;Esberg, LB;Ren, J
通讯作者：
Ren, J