DHC Corporation Laboratories, Division 2, 2-42 Hamada, Mihama-ku, Chiba 261-0025, Japan.
Toxicol In Vitro. 2023 Dec;93:105683. doi: 10.1016/j.tiv.2023.105683. Epub 2023 Aug 26.
Oxidative stress causes endothelial dysfunction, which is associated with vascular cellular aging and is causally related to cardiovascular disease pathogenesis. Preclinical studies indicate that a nicotinamide adenine dinucleotide (NAD) precursor, nicotinamide mononucleotide (NMN), alleviates oxidative stress in aged vessels, granting vasoprotective effects. However, the associated cellular mechanism remains largely unclear. In this study, we used human umbilical vein endothelial cells (HUVECs) to demonstrate that NMN inhibits oxidative stress-induced damage by activating the sirtuin 1 (SIRT1)/NAD(P)H: quinone oxidoreductase 1 (NQO-1) axis. We found that NMN inhibited HO-induced cytotoxicity and senescence-associated protein expression, such as p16 and p21. Furthermore, NMN prevented HO-induced actin cytoskeletal disorganization via inhibiting reactive oxygen species (ROS) production. NMN increased NQO-1 mRNA and protein expression that in turn was abrogated by SIRT1 inhibition, suggesting that NMN-inducible NQO-1 was associated with SIRT1 activity. SIRT1 and NQO-1 inhibition attenuated the inhibitory effect of NMN on HO-inducible cytotoxicity, senescence-related protein upregulation, and actin cytoskeletal disorganization. Our findings provide new insights into the mechanism by which NMN exerts protective effects against vascular oxidative stress.
氧化应激导致内皮功能障碍，这与血管细胞衰老有关，并与心血管疾病的发病机制有因果关系。临床前研究表明，烟酰胺腺嘌呤二核苷酸（NAD）前体烟酰胺单核苷酸（NMN）可以减轻衰老血管中的氧化应激，发挥血管保护作用。然而，相关的细胞机制在很大程度上仍不清楚。在这项研究中，我们使用人脐静脉内皮细胞（HUVEC）证明，NMN 通过激活沉默调节蛋白 1（SIRT1）/烟酰胺腺嘌呤二核苷酸（NAD（P））：醌氧化还原酶 1（NQO-1）轴来抑制氧化应激诱导的损伤。我们发现，NMN 抑制 HO 诱导的细胞毒性和衰老相关蛋白表达，如 p16 和 p21。此外，NMN 通过抑制活性氧（ROS）的产生来防止 HO 诱导的肌动蛋白细胞骨架解聚。NMN 增加了 NQO-1 mRNA 和蛋白的表达，而 SIRT1 抑制则消除了这种表达，表明 NMN 诱导的 NQO-1 与 SIRT1 活性有关。SIRT1 和 NQO-1 的抑制减弱了 NMN 对 HO 诱导的细胞毒性、衰老相关蛋白上调和肌动蛋白细胞骨架解聚的抑制作用。我们的研究结果为 NMN 发挥对血管氧化应激的保护作用的机制提供了新的见解。
