8-Hydroxy-2-deoxyguanosine prevents plaque formation and inhibits vascular smooth muscle cell activation through Rac1 inactivation.
8-Hydroxy-2-deoxyguanosine prevents plaque formation and inhibits vascular smooth muscle cell activation through Rac1 inactivation.
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DOI：
10.1016/j.freeradbiomed.2012.03.023
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发表时间：
2012-07-01
影响因子：
7.4
通讯作者：
Chung MH
中科院分区：
文献类型：
--
作者：
Huh JY;Son DJ;Lee Y;Lee J;Kim B;Lee HM;Jo H;Choi S;Ha H;Chung MH
8-羟基-2-脱氧鸟苷（8-OHdG）是一种氧化应激标志物，最近被重新发现可以抑制中性粒细胞和巨噬细胞中的Rac1，从而抑制这些细胞与Rac1相关的功能，包括通过NADPH氧化酶激活产生活性氧、吞噬、趋化和细胞因子释放。在血管平滑肌细胞（VSMCs）中，活性氧也会诱导异常增殖和迁移，从而导致动脉粥样硬化的进展。基于在动脉粥样硬化过程中吞噬细胞和VSMCs中活性氧的参与，我们假设8-OHdG可能具有抗动脉粥样硬化作用，并在实验诱导的小鼠动脉粥样硬化中验证了这一假设。部分结痂的ApoE敲除小鼠是一种生理上更相关的低流量和振荡模型，在2周内出现了晚期病变，口服8-OHdG可显著减少斑块形成、超氧化物形成、单核细胞/巨噬细胞浸润和细胞外基质（ECM）积累。在原发性VSMCs中观察到的8-OHdG的作用与8-OHdG在体内的作用一致，并且抑制血管紧张素II或血小板衍生生长因子诱导的活性氧的产生、增殖、迁移和ECM的产生。8-OHdG显著抑制了血管紧张素ii诱导的VSMC中Rac1活性，并且转染组成活性Rac1逆转了8-OHdG对VSMC活化的抑制作用。分子对接研究表明，8-OHdG稳定了Rac1 - gef复合物，表明8-OHdG与Rac1存在物理接触。这些发现高度提示8-OHdG的抗动脉粥样硬化作用是通过抑制Rac1活性介导的。总之，我们的研究结果表明口服活性8-OHdG通过抑制Rac1在体内抑制动脉粥样硬化斑块的形成和体外抑制VSMC的激活，这为动脉粥样硬化的治疗开辟了一条新的途径。
8-Hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative stress, has been recently rediscovered to inhibit Rac1 in neutrophils and macrophages, thereby inhibiting Rac1-linked functions of these cells, including reactive oxygen species production through NADPH oxidase activation, phagocytosis, chemotaxis, and cytokine release. In vascular smooth muscle cells (VSMCs), reactive oxygen species also induce abnormal proliferation and migration leading to progression of atherosclerosis. Based upon the involvement of reactive oxygen species in phagocytic cells and VSMCs during the atherosclerotic process, we hypothesized that 8-OHdG could have antiatherosclerotic action and tested this hypothesis in an experimentally induced atherosclerosis in mice. Partially ligated ApoE knockout mice, a more physiologically relevant model of low and oscillatory flow, developed an advanced lesion in 2 weeks, and orally administered 8-OHdG significantly reduced plaque formation along with reduced superoxide formation, monocyte/macrophage infiltration, and extracellular matrix (ECM) accumulation. The effects of 8-OHdG observed in primary VSMCs were consistent with the in vivo effects of 8-OHdG and were inhibitory to angiotensin II or platelet-derived growth factor-induced production of reactive oxygen species, proliferation, migration, and ECM production. Also, angiotensin II-induced Rac1 activity in VSMCs was significantly inhibited by 8-OHdG, and transfection of constitutively active Rac1 reversed the inhibitory effect of 8-OHdG on VSMC activation. Molecular docking study showed that 8-OHdG stabilizes Rac1–GEF complex, indicating the physical contact of 8-OHdG with Rac1. These findings highly suggest that the antiatherosclerotic effect of 8-OHdG is mediated by inhibition of Rac1 activity. In conclusion, our results show a novel action of orally active 8-OHdG in suppressing atherosclerotic plaque formation in vivo and VSMC activation in vitro through inhibition of Rac1, which emphasizes a new therapeutic avenue to benefit atherosclerosis.