Thyroid hormone inhibits vascular remodeling through suppression of cAMP response element binding protein activity
Thyroid hormone inhibits vascular remodeling through suppression of cAMP response element binding protein activity
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DOI：
10.1161/01.atv.0000233358.87583.01
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发表时间：
2006-09-01
影响因子：
8.7
通讯作者：
Sunagawa, Kenji
中科院分区：
文献类型：
--
作者：
Fukuyama, Kae;Ichiki, Toshihiro;Sunagawa, Kenji
目的：尽管越来越多的证据表明甲状腺功能受损是缺血性心脏病的危险因素，但甲状腺激素抗动脉粥样硬化作用的分子机制尚不清楚。我们研究了甲状腺激素是否影响血管紧张素II（Ang II）的信号通路，血管紧张素II（Ang II）在心血管疾病过程的广泛方面中起着关键作用。方法和结果-3，3 '，5-三碘-L-甲状腺原氨酸（T3）对血管平滑肌细胞（VSMCs）中Ang II诱导的细胞外信号调节蛋白激酶或p38丝裂原活化蛋白激酶的活化没有显示出显著的影响，而T3抑制Ang II诱导的cAMP反应元件（CRE）结合蛋白（CREB）的激活，CREB是一种参与血管重塑过程的核转录因子。免疫共沉淀法显示甲状腺激素受体与CREB之间存在蛋白质-蛋白质相互作用。T3降低了白细胞介素（IL）-6 mRNA的表达水平，CRE依赖性启动子活性，和蛋白质合成诱导的血管紧张素II。T3（100 μ g/100克，14天）给大鼠衰减后，减少CREB激活和BrdU incorporation.Conclusion -这些结果表明，T3抑制CREB/CRE信号通路，抑制细胞因子的表达和VSMCs增殖，这可能占，至少部分，甲状腺激素的抗动脉粥样硬化作用的颈动脉球囊损伤的新生内膜形成。
Objective - Although accumulating evidences suggest that impaired thyroid function is a risk for ischemic heart disease, the molecular mechanism of anti-atherosclerotic effects of thyroid hormone is poorly defined. We examined whether thyroid hormone affects signaling pathway of angiotensin II ( Ang II), which is critically involved in a broad aspect of cardiovascular disease process.Methods and Results - 3,3', 5- triiodo-L-thyronine (T3) did not show a significant effect on Ang II-induced activation of extracellular signal-regulated protein kinase or p38 mitogen-activated protein kinase in vascular smooth muscle cells (VSMCs), whereas T3 inhibited Ang II-induced activation of cAMP response element (CRE) binding protein ( CREB), a nuclear transcription factor involved in the vascular remodeling process. Coimmunoprecipitaion assay revealed the protein-protein interaction between thyroid hormone receptor and CREB. T3 reduced an expression level of interleukin (IL)-6 mRNA, CRE-dependent promoter activity, and protein synthesis induced by Ang II. Administration of T3 ( 100 mu g/100 g for 14 days) to rats attenuated neointimal formation after balloon injury of carotid artery with reduced CREB activation and BrdU incorporation.Conclusion - These results suggested that T3 inhibits CREB/CRE signaling pathway and suppresses cytokine expression and VSMCs proliferation, which may account for, at least in part, an anti-atherosclerotic effect of thyroid hormone.