From the Robarts Research Institute (A.W., Z.N., H.Y., C.O., R.G., J.G.P.), Division of Cardiology, Department of Medicine (J.G.P.), Department of Biochemistry (A.W., J.G.P.), Department of Medical Biophysics (B.B., J.G.P.), Department of Surgery (S.F., L.G., M.W.A.C.), and Department of Physiology and Pharmacology (R.G.), The University of Western Ontario, London Health Sciences Centre, Canada; and Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium (O.L.).
Circ Res. 2017 Jun 9;120(12):1889-1902. doi: 10.1161/CIRCRESAHA.116.310022. Epub 2017 Mar 29.
The thoracic aortic wall can degenerate over time with catastrophic consequences. Vascular smooth muscle cells (SMCs) can resist and repair artery damage, but their capacities decline with age and stress. Recently, cellular production of nicotinamide adenine dinucleotide (NAD) via nicotinamide phosphoribosyltransferase (Nampt) has emerged as a mediator of cell vitality. However, a role for Nampt in aortic SMCs in vivo is unknown.
To determine whether a Nampt-NAD control system exists within the aortic media and is required for aortic health.
Ascending aortas from patients with dilated aortopathy were immunostained for NAMPT, revealing an inverse relationship between SMC NAMPT content and aortic diameter. To determine whether a Nampt-NAD control system in SMCs impacts aortic integrity, mice with -deficient SMCs were generated. SMC- knockout mice were viable but with mildly dilated aortas that had a 43% reduction in NAD in the media. Infusion of angiotensin II led to aortic medial hemorrhage and dissection. SMCs were not apoptotic but displayed senescence associated-ß-galactosidase activity and upregulated p16, indicating premature senescence. Furthermore, there was evidence for oxidized DNA lesions, double-strand DNA strand breaks, and pronounced susceptibility to single-strand breakage. This was linked to suppressed poly(ADP-ribose) polymerase-1 activity and was reversible on resupplying NAD with nicotinamide riboside. Remarkably, we discovered unrepaired DNA strand breaks in SMCs within the human ascending aorta, which were specifically enriched in SMCs with low NAMPT. promoter analysis revealed CpG hypermethylation within the dilated human thoracic aorta and in SMCs cultured from these tissues, which inversely correlated with expression.
The aortic media depends on an intrinsic NAD fueling system to protect against DNA damage and premature SMC senescence, with relevance to human thoracic aortopathy.
随着时间的推移，胸主动脉壁可能会退化，导致灾难性的后果。血管平滑肌细胞（SMC）可以抵抗和修复动脉损伤，但它们的能力会随着年龄和压力的增加而下降。最近，通过烟酰胺磷酸核糖转移酶（Nampt）细胞内产生烟酰胺腺嘌呤二核苷酸（NAD）作为细胞活力的介质而出现。然而，Nampt 在体内主动脉平滑肌细胞中的作用尚不清楚。
确定主动脉中层是否存在 Nampt-NAD 控制系统，以及该系统是否对主动脉健康至关重要。
对扩张性主动脉病患者的升主动脉进行 NAMPT 免疫染色，结果显示 SMC NAMPT 含量与主动脉直径呈反比关系。为了确定 SMC 中的 Nampt-NAD 控制系统是否影响主动脉完整性，生成了缺乏 SMC 的小鼠。-/-小鼠具有活力，但主动脉轻度扩张，其中 NAD 在中层减少了 43%。血管紧张素 II 的输注导致主动脉中层出血和夹层。SMC 没有凋亡，但显示出衰老相关的 -半乳糖苷酶活性和上调的 p16，表明过早衰老。此外，还存在氧化 DNA 损伤、双链 DNA 链断裂和明显的单链断裂易感性的证据。这与多聚（ADP-核糖）聚合酶-1 活性受到抑制有关，并且在用烟酰胺核糖苷补充 NAD 时是可逆的。值得注意的是，我们在人类升主动脉的 SMC 中发现了未修复的 DNA 链断裂，这些断裂在 NAMPT 含量低的 SMC 中特别丰富。启动子分析显示，扩张的人类胸主动脉和从这些组织培养的 SMC 中存在 CpG 过度甲基化，与 表达呈负相关。
主动脉中层依赖于内在的 NAD 供能系统来保护 DNA 免受损伤和 SMC 过早衰老，这与人类胸主动脉病有关。
