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目的:心肌肥厚是心脏对于压力负荷或者容量负荷所产生的适应性反应。细胞色素P450表氧化酶2J2(CYP 2J2)及其代谢产物EETs可以发挥抵抗心肌肥厚的作用,而其中的机制仍有待进一步探索。方法和结果:在体内研究中,我们采用PPARα缺陷小鼠以及野生小鼠为研究对象,并采用血管紧张素Ⅱ(Ang Ⅱ)诱导小鼠发生心肌肥厚。结果表明,Ang Ⅱ可以明显诱导心肌肥厚,具体包括心脏肥大、心脏功能减低和心肌肥厚标志物表达增加。而在野生小鼠中,CYP 2J2过表达可以抑制Ang Ⅱ所诱导的心肌肥厚,但是这一抑制作用在PPARα缺陷小鼠则没有体现。在离体研究中,我们以大鼠乳鼠心肌细胞作为研究对象并采用Ang Ⅱ作为诱导因子。研究表明,外源性加入11,12-EET可明显抑制Ang Ⅱ所诱导的心肌肥大,而PPARα特异性阻断剂GW6471可以阻断11,12-EET的作用,并且这一作用可能与Ras/MAPK以及NF-κB通路有关。另外,我们通过荧光报告基因系统以及染色质免疫沉淀实验证实,PPARα可以直接结合到caveolin-1的转录子区,并诱导caveolin-1的表达,而且采用si RNA介导caveolin-1的沉默,可以抑制11,12-EET抵抗Ang Ⅱ的效应。结论:CYP 2J2及其代谢产物EETs可以通过PPARα缓解Ang Ⅱ诱导的心肌肥厚,这一作用可能与其在转录水平上调caveolin-1的表达,并进一步抑制Ras/MAPK和NF-κB通路有关。
PURPOSE: Cardiac hypertrophy is the adaptive response of the heart to stress or volume loading. Cytochrome P450 epoxidase 2J2 (CYP 2J2) and its metabolite EETs can play a role in the resistance to myocardial hypertrophy, and the mechanism remains to be further explored. Methods and Results: In vivo studies, we used PPARα-deficient mice and wild-type mice as study subjects, and used angiotensin Ⅱ (Ang Ⅱ) to induce cardiac hypertrophy in mice. The results show that Ang Ⅱ can significantly induce cardiac hypertrophy, including cardiac hypertrophy, cardiac dysfunction and increased expression of cardiac hypertrophy markers. In wild mice, CYP 2J2 overexpression can inhibit Ang Ⅱ-induced cardiac hypertrophy, but this inhibition is not demonstrated in PPARα-deficient mice. In in vitro studies, we used rat neonatal rat cardiomyocytes as a study subject and Ang II as an inducing factor. Studies have shown that exogenous addition of 11,12-EET can significantly inhibit Ang Ⅱ-induced cardiac hypertrophy, and PPARα-specific blocking agent GW6471 can block the role of 11,12-EET, and this effect may be associated with Ras / MAPK and NF-κB pathway. In addition, we confirmed by fluorescence reporter gene system and chromatin immunoprecipitation experiments that PPARα can directly bind to the caveolin-1 transcriptional region and induce the expression of caveolin-1, and siRNA can mediate the silencing of caveolin-1 Inhibit the effect of 11,12-EET on Ang Ⅱ. CONCLUSION: CYP 2J2 and its metabolite EETs can attenuate Ang Ⅱ-induced cardiac hypertrophy through PPARα, which may be related to upregulation of caveolin-1 at transcriptional level and further inhibition of Ras / MAPK and NF-κB pathway.