Li Mailin, Gallo David, Csizmadia Eva, Otterbein Leo E, Wegiel Barbara
Barbara Wegiel, PhD, Department of Surgery, Harvard Medical School, Department of Surgery, Beth Israel Deaconess Medical Center, 3 Blackfan Circle CLS #601, Boston, MA 02215, USA, Tel.: +1 617 735 2846, Fax: +1 617 735 2844, E-mail:
Thromb Haemost. 2014 May 5;111(5):951-9. doi: 10.1160/TH13-09-0748. Epub 2014 Jan 30.
Vascular injury to vessel endothelial cells (EC), caused by either mechanical damage or chronic inflammation, is still awaiting effective therapies. In the present study we hypothesised that carbon monoxide (CO) acts on the nuclear receptor Rev-erbα to induce chromatin modification and endothelial cell migration. We demonstrate that administration of low, safe doses of exogenous CO enhances endothelial cell (EC) migration, which occurs in part through chromatin remodelling and histone H3 acetylation. Further, we show that the effects of CO are dependent on inhibition of phosphorylation of glycogen synthase kinase-3 β (GSK3β), activation of haem synthesis, and increased expression of Rev-erbα. Rev-erbα is a haem-containing transcription factor which in response to CO binds to target DNA, recruits the Histone Deacetylase/nuclear Receptor Corepressor (HDAC/N-CoR) complex, and regulates transcription of genes responsible for endothelial cell migration and angiogenesis. Decreased levels of Rev-erbα in chimeric mice after bone marrow transplant from Rev-erbα following bone marrow transplantation from rev-erb+/- mice resulted in loss of protective effects of CO against neointima formation after wire injury. Collectively, CO modifies chromatin structure through enhanced acetylation of histone H3 via a GSK3β-Rev-erbα-mediated pathway to increase EC migration. We propose that CO enhances vessel repair following injury in part by regulating EPC/EC motility via Rev-erbα. Thus, inhaled CO may be beneficial in the treatment of vascular syndromes associated with dysregulated thrombosis, wound healing, and angiogenesis.
由机械损伤或慢性炎症引起的血管内皮细胞（EC）的血管损伤，仍在等待有效的治疗方法。在本研究中，我们假设一氧化碳（CO）作用于核受体Rev-erbα以诱导染色质修饰和内皮细胞迁移。我们证明，给予低剂量、安全剂量的外源性CO可增强内皮细胞（EC）迁移，这部分是通过染色质重塑和组蛋白H3乙酰化实现的。此外，我们表明CO的作用依赖于糖原合酶激酶-3β（GSK3β）磷酸化的抑制、血红素合成的激活以及Rev-erbα表达的增加。Rev-erbα是一种含血红素的转录因子，其响应CO与靶DNA结合，募集组蛋白去乙酰化酶/核受体共抑制因子（HDAC/N-CoR）复合物，并调节负责内皮细胞迁移和血管生成的基因的转录。从rev-erb+/-小鼠骨髓移植后，嵌合小鼠中Rev-erbα水平降低，导致CO对钢丝损伤后新内膜形成的保护作用丧失。总的来说，CO通过GSK3β-Rev-erbα介导的途径增强组蛋白H3的乙酰化来修饰染色质结构，以增加EC迁移。我们提出，CO部分通过Rev-erbα调节EPC/EC运动性来增强损伤后的血管修复。因此，吸入CO可能有益于治疗与血栓形成失调、伤口愈合和血管生成相关的血管综合征。
