Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
Toxicol In Vitro. 2010 Apr;24(3):863-71. doi: 10.1016/j.tiv.2009.12.002. Epub 2009 Dec 5.
Cigarette smoke is a major risk factor for cardiovascular diseases. It contains thousands of compounds that activate the aryl hydrocarbon receptor (AhR). In addition, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent AhR ligand, has been shown to cause cardiotoxic effects in several in vivo models. Although induction of CYP1 family is the most important effect of AhR activation, the role of CYP1 induction in mediating the cardiotoxic effect of TCDD is usually overlooked. Therefore, we investigated whether AhR activation causes a hypertrophic effect in H9c2 cells and we related this effect to changes in CYP gene expression. In the current study, the cardiac derived H9c2 cells were treated with two AhR ligands, TCDD and beta-naphthoflavone (BNF), for 24 and 48h. The expression of the hypertrophic markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), and several CYP genes were measured by real-time PCR. Treatment of H9c2 cells with TCDD or BNF for 24h caused a significant induction of CYP1A1, CYP1B1, and CYP4A1; however, there was no change in the expression of other genes. On the other hand, treatment of the cells with TCDD or BNF for 48h caused a significant induction of the hypertrophic markers, ANP and BNP, and several CYP genes such as CYP1A1, CYP1B1, CYP2E1, CYP2J3, and CYP4F4 parallel to a significant increase in the cell surface area. Neither TCDD nor BNF increased the oxidative stress in H9c2 cells at all concentrations tested. Interestingly, resveratrol, an AhR antagonist, protected the cells from TCDD-induced hypertrophy. In conclusion, AhR ligands caused a hypertrophic effect in H9c2 cells which was associated with induction of several CYP genes which can be prevented by resveratrol.
香烟烟雾是心血管疾病的主要危险因素。它含有数千种化合物，可激活芳香烃受体 (AhR)。此外，2,3,7,8-四氯二苯并对二恶英 (TCDD)，即最强的 AhR 配体，已被证明在几种体内模型中引起心脏毒性作用。虽然 CYP1 家族的诱导是 AhR 激活的最重要作用，但 CYP1 诱导在介导 TCDD 的心脏毒性作用中的作用通常被忽视。因此，我们研究了 AhR 激活是否会导致 H9c2 细胞肥大，并将这种作用与 CYP 基因表达的变化相关联。在本研究中，用两种 AhR 配体 TCDD 和β-萘黄酮 (BNF) 处理心肌源性 H9c2 细胞 24 和 48 小时。通过实时 PCR 测量肥大标志物心房利钠肽 (ANP) 和脑利钠肽 (BNP) 和几种 CYP 基因的表达。用 TCDD 或 BNF 处理 H9c2 细胞 24 小时会导致 CYP1A1、CYP1B1 和 CYP4A1 的显著诱导；然而，其他基因的表达没有变化。另一方面，用 TCDD 或 BNF 处理细胞 48 小时会导致肥大标志物 ANP 和 BNP 以及几种 CYP 基因（如 CYP1A1、CYP1B1、CYP2E1、CYP2J3 和 CYP4F4）的显著诱导，同时细胞表面积显著增加。在所有测试浓度下，TCDD 或 BNF 均未增加 H9c2 细胞的氧化应激。有趣的是，白藜芦醇，一种 AhR 拮抗剂，可防止细胞发生 TCDD 诱导的肥大。总之，AhR 配体在 H9c2 细胞中引起肥大作用，这与几种 CYP 基因的诱导有关，白藜芦醇可预防这种诱导。
