Boosting NAD level suppresses inflammator activation of PBMCs in heart failure
Boosting NAD level suppresses inflammator activation of PBMCs in heart failure
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DOI：
10.1172/jci138538
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发表时间：
2020-11-02
影响因子：
15.9
通讯作者：
Tian, Rong
中科院分区：
文献类型：
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作者：
Zhou, Bo;Wang, Dennis Ding-Hwa;Tian, Rong
背景资料。虽然线粒体在先天免疫中发挥着重要作用，但线粒体功能障碍与心力衰竭(HF)炎症之间的关系却知之甚少。在本研究中，我们旨在探讨外周血单个核细胞(PBMC)线粒体功能障碍与炎症激活之间的机制联系，以及提高NAD水平的潜在抗炎作用。19例D期心力衰竭住院患者和19例健康体检者的呼吸情况。然后，我们通过用线粒体治疗健康的PBMC，建立了一个无菌炎症的体外模型！从人心脏组织中分离的损伤相关分子模式(MitoDAMPs)。最后，我们招募了心力衰竭阶段的患者，并在服用S的9天前和9天后采集了他们的血液样本。结果：我们证明了心力衰竭与呼吸能力降低和促炎细胞因子基因表达增加有关。在我们的体外模型中，MitoDAMP处理的PBMC分泌IL-6，损害线粒体！通过减少复合体i的活性来进行呼吸。最后，口服NR促进了4例HF患者的PBMC呼吸，降低了促炎细胞因子基因的表达。结论这些发现提示HF患者的全身炎症与线粒体有关！PBMCs的功能。增加NAD水平可能有可能改善线粒体呼吸，并减弱HF时PBMCs的促炎活性。
BACKGROUND. While mitochondria play an important role in innate immunity, the relationship between mitochondria; dysfunction and inflammation in heart failure (HF) is poorly understood. In this study we aimed to investigate the mechanistic link between mitochondrial dysfunction and inflammatory activation in peripheral blood mononuclear cells (PBMCs), and the potential antiinflammatory effect of boosting the NAD level.METHODS. We compared the PBMC mitochondria! respiration of 19 hospitalized patients with stage D HF with that of 19 healthy participants. We then created an in vitro model of sterile inflammation by treating healthy PBMCs with mitochondria! damage-associated molecular patterns (MitoDAMPs) isolated from human heart tissue. Last, we enrolled patients with stage HF and sampled their blood before and after taking S to 9 days of oral nicotinamide riboside (NR), a NAD precursor.RESULTS. We demonstrated that HF is associated with both reduced respiratory capacity and elevated proinflammatory cytokine gene expressions. In our in vitro model, MitoDAMP-treated PBMCs secreted IL-6 that impaired mitochondria! respiration by reducing complex I activity. Last, oral NR administration enhanced PBMC respiration and reduced proinflammatory cytokine gene expression in 4 subjects with HF.CONCLUSION. These findings suggest that systemic inflammation in patients with HF is causally linked to mitochondria! function of the PBMCs. Increasing NAD levels may have the potential to improve mitochondrial respiration and attenuate proinflammatory activation of PBMCs in HF.