Gene delivery of cytochrome p450 epoxygenase ameliorates monocrotaline-induced pulmonary artery hypertension in rats.
Gene delivery of cytochrome p450 epoxygenase ameliorates monocrotaline-induced pulmonary artery hypertension in rats.
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DOI：
10.1165/rcmb.2009-0161oc
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发表时间：
2010-01
影响因子：
6.4
通讯作者：
Changlong Zheng;Luyun Wang;Rui Li;Ben Ma;L. Tu;Xizhen Xu;Ryan T. Dackor;D. Zeldin;Daowen Wang
中科院分区：
文献类型：
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作者：
Changlong Zheng;Luyun Wang;Rui Li;Ben Ma;L. Tu;Xizhen Xu;Ryan T. Dackor;D. Zeldin;Daowen Wang
肺动脉高压（PAH）是一种危及生命的疾病，可导致进行性肺动脉高压、右心衰竭和死亡。内皮功能障碍和炎症与PAH的发病机制有关。环氧二十碳三烯酸（Epoxyeicosatrienoic acids，EAE）是花生四烯酸经细胞色素P450表氧化酶代谢后的产物，具有抗炎和保护内皮细胞的作用。我们研究了人细胞色素P450表氧化酶2 J2（CYP 2 J2）基因转染是否能改善野百合碱（MCT）诱导的大鼠肺动脉高压。MCT给药后3周出现显著的肺动脉高压，但CYP 2 J2基因治疗可显著减弱肺动脉高压和肺血管重塑的发生，而不会引起全身动脉压或心率的变化。这些作用与肺内皮NO合酶（eNOS）表达及其活性增加、肺部炎症抑制以及转化生长因子（TGF）-β/II型骨形态发生蛋白受体（BMPRII）-果蝇母体对抗十肢麻痹蛋白（Smads）信号传导有关。总的来说，这些数据表明，CYP 2 J2的基因治疗可能有潜力作为一种新的治疗方法，这种渐进的，往往是致命的疾病。
Pulmonary arterial hypertension (PAH) is a life-threatening disease that leads to progressive pulmonary hypertension, right heart failure, and death. Endothelial dysfunction and inflammation were implicated in the pathogenesis of PAH. Epoxyeicosatrienoic acids (EETs), products of the cytochrome P450 epoxygenase metabolism of arachidonic acid, are potent vasodilators that possess anti-inflammatory and other protective properties in endothelial cells. We investigated whether gene delivery with the human cytochrome P450 epoxygenase 2J2 (CYP2J2) ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Significant pulmonary hypertension developed 3 weeks after the administration of MCT, but gene therapy with CYP2J2 significantly attenuated the development of pulmonary hypertension and pulmonary vascular remodeling, without causing changes in systemic arterial pressure or heart rate. These effects were associated with increased pulmonary endothelial NO synthase (eNOS) expression and its activity, inhibition of inflammation in the lungs, and transforming growth factor (TGF)-β/type II bone morphogenetic protein receptor (BMPRII)-drosophila mothers against decapentaplegic proteins (Smads) signaling. Collectively, these data suggest that gene therapy with CYP2J2 may have potential as a novel therapeutic approach to this progressive and oftentimes lethal disorder.