Estrogen-related receptor α1 up-regulates endothelial nitric oxide synthase expression
Estrogen-related receptor α1 up-regulates endothelial nitric oxide synthase expression
复制标题
DOI：
10.1073/pnas.2235590100
复制
发表时间：
2003-11-25
影响因子：
11.1
通讯作者：
Ignarro, LJ
中科院分区：
文献类型：
--
作者：
Sumi, D;Ignarro, LJ
人雌激素相关受体α 1（ERRalpha 1）是与雌激素受体密切相关的孤儿受体家族的成员。研究表明，雌激素通过内皮细胞中的雌激素受体调节内皮型一氧化氮合酶（eNOS）的表达。然而，很少有人知道ERRalpha 1和eNOS之间的关系。在这项研究中，我们发现ERRalpha 1激活雌激素反应元件（ERE）和eNOS启动子依赖的荧光素酶活性在COS-7细胞和牛肺动脉内皮细胞。ERRalpha 1的内源性配体尚未确定，但我们表明，这些行动是依赖于血清成分，因为ERRalpha 1未能刺激eNOS启动子依赖性荧光素酶活性在活性炭处理的血清。此外，通过使用截短的eNOS启动子荧光素酶构建体，我们证明ERRalpha 1对eNOS转录的激活是通过三个区域介导的：eNOS启动子上的碱基对-1001至-743，碱基对-743至-265，以及碱基对-265的下游。此外，ERRalpha 1上调eNOS mRNA和蛋白表达，并刺激牛肺动脉内皮细胞中eNOS活性。这些结果表明，ERRalpha 1在eNOS表达的调节中具有潜在的作用，并且可以刺激内皮细胞产生NO，这反过来可能导致对动脉粥样硬化的保护作用。
The human estrogen-related receptor alpha1 (ERRalpha1) is a member of an orphan receptor family closely related to the estrogen receptor. It has been demonstrated that estrogen modulates endothelial nitric oxide synthase (eNOS) expression through the estrogen receptor in endothelial cells. However, little is known about the relationship between ERRalpha1 and eNOS. In this study, we show that ERRalpha1 activates the estrogen response element (ERE) and eNOS promoter-dependent luciferase activity in COS-7 cells and bovine pulmonary artery endothelial cells. The endogenous ligand for ERRalpha1 has not been identified, but we show that these actions are dependent on serum constituents because ERRalpha1 fails to stimulate eNOS promoter-dependent luciferase activity in charcoal-treated serum. Furthermore, through the use of truncated eNOS promoter luciferase constructs, we demonstrate that the activation of eNOS transcription by ERRalpha1 is mediated via three regions: base pairs -1001 to -743, base pairs -743 to -265, and downstream from base pair -265 on the eNOS promoter. In addition, ERRalpha1 upregulates eNOS mRNA and protein expression and stimulates eNOS activity in bovine pulmonary artery endothelial cells. These results suggest that ERRalpha1 has a potential role in the regulation of eNOS expression and may stimulate NO production by endothelial cells, which may in turn result in a protective effect against atherosclerosis.