細胞色素P450 2E1(CYP2E1)是細胞色素P450超家族成員之一,其主要參與內(nèi)外源物質(zhì)的代謝活化。CYP2E1在多種心臟疾病情況表達增高,包括高血壓及擴張型心肌病。中國醫(yī)學(xué)科學(xué)院醫(yī)學(xué)實驗動物研究所,衛(wèi)生部人類疾病比較醫(yī)學(xué)重點實驗室張連峰實驗室(呂丹、馬元武共同第一作者)研究發(fā)現(xiàn)CYP2E1表達下調(diào)可顯著改善cTnTR41W轉(zhuǎn)基因及阿霉素誘導(dǎo)的擴張型心肌病小鼠模型心室擴張,室壁變薄及收縮功能障礙等病理表型,氧化應(yīng)激、caspase-3、-9、細胞色素c的釋放及心肌細胞凋亡亦有顯著下調(diào),即CYP2E1通過誘導(dǎo)氧化應(yīng)激及凋亡惡化心肌病病理進程,所以抑制CYP2E1的表達可能成為由cTnTR141W基因突變或其他原因?qū)е碌臄U張型心肌病的有效治療措施。這部分研究結(jié)果發(fā)表在了Hypertension雜志上(Hypertension. 2012 Jul; 60(1): 81-89.),并且被評為當(dāng)期的封面文章(圖1)
圖1. 發(fā)表于
Hypertension雜志的封面文章截圖
原文:Lu D, Ma Y, Zhang W, Bao D, Dong W, Lian H, Huang L, Zhang L. Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnTR141W Dilated Cardiomyopathy Transgenic Mice. Hypertension. 2012 Jul; 60(1): 81-89.
Abstract
Cytochrome P450 2E1 (CYP2E1) is a cytochrome P450 enzyme that catalyzes the metabolism of toxic substrates. CYP2E1 is upregulated in heart disease, including the dilated cardiomyopathy (DCM) mouse model. Here, knockdown of CYP2E1 significantly ameliorated the dilated left ventricle, thin wall, and dysfunctional contraction in the cTnT(R141W) and adriamycin-induced DCM mouse models. Interstitial fibrosis, poorly organized myofibrils, and swollen mitochondria with loss of cristae were improved in the myocardium of α-myosin heavy chain (MHC)-cTnT(R141W)×CYP2E1-silence double-transgenic mice when compared with the cTnT(R141W) transgenic mice. Oxidative stress, the activation of caspase 3 and caspase 9, the release of cytochrome c, and the apoptosis in the myocardium were significantly decreased in double-transgenic mice compared with the cTnT(R141W) transgenic mice. In summary, the expression of CYP2E1 is upregulated in heart disease and might be induced by hypoxemia in cardiomyopathy. The overexpression of CYP2E1 can enhance the metabolism of endogenous ketones to meet the energy demand of the heart in certain disease states, but the overexpression of CYP2E1 can also increase oxidative stress and apoptosis in the DCM heart. Knockdown or downregulation of CYP2E1 might be a therapeutic strategy to control the development of DCM after mutations of cTnT(R141W) or other factors, because DCM is the third most common cause of heart failure and the most frequent cause of heart transplantation.