Several reports demonstrated the direct contribution of cytochrome P450 1B1 (CYP1B1) enzyme and its associated cardiotoxic mid-chain, hydroxyeicosatetraenoic acid (HETEs) metabolites in the development of cardiac hypertrophy. Resveratrol is commercially available polyphenol that exerts beneficial effects in wide array of cardiovascular diseases including cardiac hypertrophy, myocardial infarction and heart failure. Nevertheless, the underlying mechanisms responsible for these effects are not fully elucidated. Since resveratrol is a well-known CYP1B1 inhibitor, the purpose of this study is to test whether resveratrol attenuates angiotensin II (Ang II)-induced cellular hypertrophy through inhibition of CYP1B1/mid-chain HETEs mechanism. RL-14 and H9c2 cells were treated with vehicle or 10 μM Ang II in the absence and presence of 2, 10 or 50 μM resveratrol for 24 h. Thereafter, the level of mid-chain HETEs was determined using liquid chromatography–mass spectrometry (LC/MS). Hypertrophic markers and CYP1B1 gene expression and protein levels were measured using real-time PCR and Western blot analysis, respectively. Our results demonstrated that resveratrol, at concentrations of 10 and 50 μM, was able to attenuate Ang-II-induced cellular hypertrophy as evidenced by substantial inhibition of hypertrophic markers, β-myosin heavy chain (MHC)/α-MHC and atrial natriuretic peptide. Ang II significantly induced the protein expression of CYP1B1 and increased the metabolite formation rate of its associated mid-chain HETEs. Interestingly, the protective effect of resveratrol was associated with a significant decrease of CYP1B1 protein expression and mid-chain HETEs. Our results provided the first evidence that resveratrol protects against Ang II-induced cellular hypertrophy, at least in part, through CYP1B1/mid-chain HETEs-dependent mechanism.

几篇报道证明了细胞色素P450 1B1（CYP1B1）酶及其相关的心脏毒性中链羟基二十碳四烯酸（HETEs）代谢产物在心脏肥大过程中的直接贡献。白藜芦醇是可商购的多酚，可在多种心血管疾病中发挥有益作用，包括心脏肥大，心肌梗塞和心力衰竭。但是，尚未完全阐明造成这些影响的潜在机制。由于白藜芦醇是众所周知的CYP1B1抑制剂，因此本研究的目的是测试白藜芦醇是否通过抑制CYP1B1 /中链HETEs机制来减轻血管紧张素II（Ang II）诱导的细胞肥大。在不存在和存在2的情况下，用媒介物或10μMAng II处理RL-14和H9c2细胞，10或50μM白藜芦醇24小时。此后，使用液相色谱-质谱法（LC / MS）确定中链HETE的水平。使用实时荧光定量PCR和蛋白质印迹分析分别检测肥厚性标志物，CYP1B1基因表达和蛋白水平。我们的研究结果表明，浓度为10和50μM的白藜芦醇能够减弱Ang-II诱导的细胞肥大，这被肥大标志物，β-肌球蛋白重链（MHC）/α-MHC和心钠素显着抑制所证明。 。Ang II显着诱导CYP1B1的蛋白表达，并增加其相关的中链HETE的代谢物形成速率。有趣的是，白藜芦醇的保护作用与CYP1B1蛋白表达和中链HETE的显着降低有关。