2,3,7,8-Tetrachlorodibenzo-p-dioxin promotes injury-induced vascular neointima formation in mice
2,3,7,8-Tetrachlorodibenzo-p-dioxin promotes injury-induced vascular neointima formation in mice
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2,3,7,8-四氯二苯并-对二恶英促进小鼠损伤诱导的血管新内膜形成
DOI：
10.1096/fj.201900546r
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发表时间：
2019-09-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Guo, Shumin;Zhang, Rui;Zhang, Jian
2，3，7，8-四氯二苯并对二恶英（TCDD）是一种引起心血管毒性的环境污染物。血管平滑肌细胞（VSMC）从收缩型向合成型的表型转化是血管对损伤反应的标志。然而，TCDD在血管重构中的确切作用和分子机制仍不清楚。在本研究中，我们发现TCDD处理促进小鼠血管平滑肌细胞表型从收缩型向合成型的转变，并加剧了钢丝损伤后的血管新生内膜增生。TCDD处理可促进VSMC从G 0/G1期进入S期和G2/M期。细胞周期蛋白D1、细胞周期蛋白依赖性激酶4（CDK 4）及其磷酸化的表达在TCDD处理后协同增加。敲低芳烃受体（AHR）可抑制TCDD诱导的VSMC表型转变，促进S/G2期细胞周期阻滞。TCDD处理显著增加VSMCs致癌c-Jun基因表达。ChIP法显示AHR与c-Jun启动子直接结合，上调c-Jun mRNA的表达，沉默c-Jun基因可增强p53和p21的表达，抑制CDK 4和cyclin D1的表达，从而抑制TCDD刺激的VSMC增殖和合成表型转变。体内研究表明，在TCDD处理的小鼠中，VSMC中c-Jun的基因去除限制了损伤诱导的新生内膜增生。因此，TCDD暴露通过激活AHR和上调其靶基因c-Jun的表达来夸大损伤诱导的血管重塑，这表明抑制AHR可能是TCDD相关心血管疾病的有希望的预防策略。Guo，S.，Zhang，R.，Liu，Q.，Wan，Q.，Wang，Y.，Yu，Y.，Liu，G.，沈，Y.，Yu，Y.，Zhang，J. 2，3，7，8-四氯二苯并对二恶英促进小鼠损伤诱导的血管新生内膜形成。
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental pollutant that causes cardiovascular toxicity. The phenotypic transformation of vascular smooth muscle cells (VSMCs) from the contractile to the synthetic phenotype is a hallmark of vascular response to injury. However, the precise role and molecular mechanism of TCDD in vascular remodeling remains unknown. In the present study, we found that TCDD treatment promoted VSMC phenotypic transition from contractile to synthetic phenotype and exaggerated vascular neointimal hyperplasia after wire injury in mice. TCDD treatment enhanced VSMC entry into cell cycle from G0/G1 phase to S and G2/M phase. The expression of cyclin D1, cyclin-dependent kinase 4 (CDK4), and its phosphorylation were coordinately increased in response to TCDD treatment. Knocking down of aryl hydrocarbon receptor (AHR) inhibited VSMC phenotypic transition induced by TCDD and promoted S/G2 phase cell cycle arrest. TCDD treatment markedly increased oncogenic c-Jun gene expression in VSMCs. ChIP assay revealed the direct binding of AHR on the promoter of c-Jun to up-regulate the mRNA expression of c-Jun. Silencing of c-Jun gene enhanced the expression of p53 and p21, whereas attenuated the expression of CDK4 and cyclin D1 leading to the decrease in the TCDD-stimulated VSMC proliferation and synthetic phenotype transition in vitro. In vivo study showed that genetic ablation of c-Jun in VSMCs restricted injury-induced neointimal hyperplasia in TCDD-treated mice. Thus, TCDD exposure exaggerated injury-induced vascular remodeling by the activation of AHR and up-regulation of the expression of its target gene c-Jun, indicating that inhibition of AHR may be a promising prevention strategy for TCDD-associated cardiovascular diseases.-Guo, S., Zhang, R., Liu, Q., Wan, Q., Wang, Y., Yu, Y., Liu, G., Shen, Y., Yu, Y., Zhang, J. 2,3,7,8-Tetrachlorodibenzo-p-dioxin promotes injury-induced vascular neointima formation in mice.