Saha Cardiovascular Research Center, University of Kentucky, 900 S Limestone St., Lexington, KY 40536-0200, USA.
Arterioscler Thromb Vasc Biol. 2011 Feb;31(2):245-52. doi: 10.1161/ATVBAHA.110.219808. Epub 2010 Nov 24.
Telomerase serves as a critical regulator of tissue renewal. Although telomerase activity is inducible in response to various environmental cues, it remains unknown whether telomerase is activated during the inflammatory remodeling underlying atherosclerosis formation. To address this question, we investigated in the present study the regulation of telomerase in macrophages and during atherosclerosis development in low-density lipoprotein receptor-deficient mice.
We demonstrate that inflammatory stimuli activate telomerase in macrophages by inducing the expression of the catalytic subunit telomerase reverse transcriptase (TERT). Reporter and chromatin immunoprecipitation assays identified a previously unrecognized nuclear factor-κB (NF-κB) response element in the TERT promoter, to which NF-κB is recruited during inflammation. Inhibition of NF-κB signaling completely abolished the induction of TERT expression, characterizing TERT as a bona fide NF-κB target gene. Furthermore, functional experiments revealed that TERT deficiency results in a senescent cell phenotype. Finally, we demonstrate high levels of TERT expression in macrophages of human atherosclerotic lesions and establish that telomerase is activated during atherosclerosis development in low-density lipoprotein receptor-deficient mice.
These results characterize TERT as a previously unrecognized NF-κB target gene in macrophages and demonstrate that telomerase is activated during atherosclerosis. This induction of TERT expression prevents macrophage senescence and may have important implications for the development of atherosclerosis.
端粒酶作为组织更新的关键调节因子。虽然端粒酶活性可响应各种环境线索诱导，但尚不清楚在动脉粥样硬化形成所涉及的炎症重塑过程中端粒酶是否被激活。为了解决这个问题，本研究调查了在低密度脂蛋白受体缺陷小鼠中巨噬细胞中以及动脉粥样硬化发展过程中端粒酶的调节。
我们证明，炎症刺激通过诱导端粒酶逆转录酶（TERT）的表达，在巨噬细胞中激活端粒酶。报告基因和染色质免疫沉淀分析鉴定了 TERT 启动子中一个先前未被识别的核因子-κB（NF-κB）反应元件，在炎症过程中 NF-κB 被募集到该元件。NF-κB 信号通路的抑制完全消除了 TERT 表达的诱导，将 TERT 确认为一个真正的 NF-κB 靶基因。此外，功能实验表明 TERT 缺陷导致衰老细胞表型。最后，我们证明了人动脉粥样硬化病变中巨噬细胞中 TERT 的高表达，并证实了在低密度脂蛋白受体缺陷小鼠中动脉粥样硬化发展过程中端粒酶的激活。
这些结果将 TERT 确定为巨噬细胞中以前未被识别的 NF-κB 靶基因，并证明了端粒酶在动脉粥样硬化中被激活。这种 TERT 表达的诱导可防止巨噬细胞衰老，可能对动脉粥样硬化的发展具有重要意义。
