Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice.
Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice.
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DOI：
10.1111/acel.12461
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发表时间：
2016-06
期刊：
影响因子：
7.8
通讯作者：
Seals DR
中科院分区：
文献类型：
--
作者：
de Picciotto NE;Gano LB;Johnson LC;Martens CR;Sindler AL;Mills KF;Imai S;Seals DR
我们测试了一种假设，即补充一种关键的NAD +中间体烟酰胺单甘肽（NMN）可增加动脉SIRT 1活性并逆转与年龄相关的动脉功能障碍和氧化应激。与年轻小鼠（YC）相比，老年对照小鼠（OC）颈动脉内皮依赖性扩张（EDD）（60 ± 5% vs. 84 ± 2%）受损，这是一种内皮功能指标，一氧化氮（NO）介导的EDD（37 ± 4% vs. 66 ± 6%）受损。这种与年龄相关的EDD损伤在OC中被超氧化物清除剂TEMPOL恢复（82 ± 7%）。与YC相比，OC还增加了主动脉脉搏波速度（aPWV，464 ± 31 cm s-1 vs. 337 ± 3 cm s-1）和弹性模量（EM，6407 ± 876 kPa vs. 3119 ± 471 kPa），测量大弹性动脉硬度。与YC相比，OC具有更高的主动脉生成（2.0 ± 0.1 vs. 1.0 ± 0.1 Au）、硝基酪氨酸丰度（氧化应激的标志物）和I型胶原，以及降低的弹性蛋白和血管SIRT 1活性（通过NFκB的p65亚基的乙酰化状态测量）。在老年小鼠中补充NMN可恢复EDD（86 ± 2%）和NO介导的EDD（61 ± 5%），降低aPWV（359 ± 14 cm s−1）和EM（3694 ± 315 kPa），使产量正常化（0.9 ± 0.1 Au），减少硝基酪氨酸，逆转胶原蛋白I，增加弹性蛋白，并恢复血管SIRT 1活性。急性NMN孵育在孤立的Aesthetas增加NAD +三倍，锰超氧化物歧化酶（MnSOD）的50%。NMN补充可能是一种通过降低氧化应激来恢复SIRT 1活性和逆转年龄相关动脉功能障碍的新疗法。
We tested the hypothesis that supplementation of nicotinamide mononucleotide (NMN), a key NAD + intermediate, increases arterial SIRT1 activity and reverses age‐associated arterial dysfunction and oxidative stress. Old control mice (OC) had impaired carotid artery endothelium‐dependent dilation (EDD) (60 ± 5% vs. 84 ± 2%), a measure of endothelial function, and nitric oxide (NO)‐mediated EDD (37 ± 4% vs. 66 ± 6%), compared with young mice (YC). This age‐associated impairment in EDD was restored in OC by the superoxide () scavenger TEMPOL (82 ± 7%). OC also had increased aortic pulse wave velocity (aPWV, 464 ± 31 cm s−1 vs. 337 ± 3 cm s−1) and elastic modulus (EM, 6407 ± 876 kPa vs. 3119 ± 471 kPa), measures of large elastic artery stiffness, compared with YC. OC had greater aortic production (2.0 ± 0.1 vs. 1.0 ± 0.1 AU), nitrotyrosine abundance (a marker of oxidative stress), and collagen‐I, and reduced elastin and vascular SIRT1 activity, measured by the acetylation status of the p65 subunit of NFκB, compared with YC. Supplementation with NMN in old mice restored EDD (86 ± 2%) and NO‐mediated EDD (61 ± 5%), reduced aPWV (359 ± 14 cm s−1) and EM (3694 ± 315 kPa), normalized production (0.9 ± 0.1 AU), decreased nitrotyrosine, reversed collagen‐I, increased elastin, and restored vascular SIRT1 activity. Acute NMN incubation in isolated aortas increased NAD + threefold and manganese superoxide dismutase (MnSOD) by 50%. NMN supplementation may represent a novel therapy to restore SIRT1 activity and reverse age‐related arterial dysfunction by decreasing oxidative stress.