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Nitric Oxide Suppresses β-Cell Apoptosis by Inhibiting the DNA Damage Response

机译：一氧化氮通过抑制DNA损伤反应抑制β细胞凋亡

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Nitric oxide, produced in pancreatic β cells in response to proinflammatory cytokines, plays a dual role in the regulation of β-cell fate. While nitric oxide induces cellular damage and impairs β-cell function, it also promotes β-cell survival through activation of protective pathways that promote β-cell recovery. In this study, we identify a novel mechanism in which nitric oxide prevents β-cell apoptosis by attenuating the DNA damage response (DDR). Nitric oxide suppresses activation of the DDR (as measured by γH2AX formation and the phosphorylation of KAP1 and p53) in response to multiple genotoxic agents, including camptothecin, H2O2, and nitric oxide itself, despite the presence of DNA damage. While camptothecin and H2O2 both induce DDR activation, nitric oxide suppresses only camptothecin-induced apoptosis and not H2O2-induced necrosis. The ability of nitric oxide to suppress the DDR appears to be selective for pancreatic β cells, as nitric oxide fails to inhibit DDR signaling in macrophages, hepatocytes, and fibroblasts, three additional cell types examined. While originally described as the damaging agent responsible for cytokine-induced β-cell death, these studies identify a novel role for nitric oxide as a protective molecule that promotes β-cell survival by suppressing DDR signaling and attenuating DNA damage-induced apoptosis.
机译：一氧化氮在胰腺β细胞中响应促炎性细胞因子而产生，在调节β细胞命运中起着双重作用。一氧化氮会诱导细胞损伤并损害β细胞功能，但它也会通过激活促进β细胞恢复的保护性途径来促进β细胞存活。在这项研究中，我们确定了一种新的机制，其中一氧化氮通过减弱DNA损伤反应（DDR）来防止β细胞凋亡。一氧化氮抑制DDR的激活（通过γH2AX的形成以及KAP1和p53的磷酸化来衡量），它响应喜树碱，H 2 O 2 等多种遗传毒性剂，和一氧化氮本身，尽管存在DNA损伤。喜树碱和H 2 O 2 均能诱导DDR激活，而一氧化氮仅抑制喜树碱诱导的细胞凋亡而不抑制H 2 O 2 引起的坏死。一氧化氮抑制DDR的能力似乎对胰腺β细胞具有选择性，因为一氧化氮无法抑制巨噬细胞，肝细胞和成纤维细胞中的DDR信号传导，这是另外三种细胞类型。虽然最初被描述为造成细胞因子诱导的β细胞死亡的破坏剂，但这些研究发现一氧化氮作为一种保护分子，通过抑制DDR信号传导和减弱DNA损伤诱导的细胞凋亡来促进β细胞存活，具有新的作用。

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