Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Department of Vascular Biology Center, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.
Cardiovasc Res. 2020 Dec 1;116(14):2226-2238. doi: 10.1093/cvr/cvz303.
Chronic adventitial and medial infiltration of immune cells play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). Nicotinic acid (niacin) was shown to inhibit atherosclerosis by activating the anti-inflammatory G protein-coupled receptor GPR109A [also known as hydroxycarboxylic acid receptor 2 (HCA2)] expressed on immune cells, blunting immune activation and adventitial inflammatory cell infiltration. Here, we investigated the role of niacin and GPR109A in regulating AAA formation.
Mice were supplemented with niacin or nicotinamide, and AAA was induced by angiotensin II (AngII) infusion or calcium chloride (CaCl2) application. Niacin markedly reduced AAA formation in both AngII and CaCl2 models, diminishing adventitial immune cell infiltration, concomitant inflammatory responses, and matrix degradation. Unexpectedly, GPR109A gene deletion did not abrogate the protective effects of niacin against AAA formation, suggesting GPR109A-independent mechanisms. Interestingly, nicotinamide, which does not activate GPR109A, also inhibited AAA formation and phenocopied the effects of niacin. Mechanistically, both niacin and nicotinamide supplementation increased nicotinamide adenine dinucleotide (NAD+) levels and NAD+-dependent Sirt1 activity, which were reduced in AAA tissues. Furthermore, pharmacological inhibition of Sirt1 abrogated the protective effect of nicotinamide against AAA formation.
Niacin protects against AAA formation independent of GPR109A, most likely by serving as an NAD+ precursor. Supplementation of NAD+ using nicotinamide-related biomolecules may represent an effective and well-tolerated approach to preventing or treating AAA.
免疫细胞的慢性外膜和中膜浸润在腹主动脉瘤（AAA）的发病机制中起着重要作用。烟酸（烟酰胺酸）通过激活免疫细胞上表达的抗炎 G 蛋白偶联受体 GPR109A[也称为羟基羧酸受体 2（HCA2）]，抑制动脉粥样硬化，从而抑制免疫激活和外膜炎症细胞浸润。在这里，我们研究了烟酸和 GPR109A 在调节 AAA 形成中的作用。
用烟酸或烟酰胺补充小鼠，并用血管紧张素 II（AngII）输注或氯化钙（CaCl2）应用诱导 AAA。烟酸在 AngII 和 CaCl2 模型中均显著减少 AAA 的形成，减少外膜免疫细胞浸润、伴随的炎症反应和基质降解。出乎意料的是，GPR109A 基因缺失并没有消除烟酸对 AAA 形成的保护作用，这表明存在 GPR109A 非依赖性机制。有趣的是，不激活 GPR109A 的烟酰胺也抑制 AAA 的形成，并模拟了烟酸的作用。从机制上讲，烟酸和烟酰胺的补充均增加了烟酰胺腺嘌呤二核苷酸（NAD+）水平和 NAD+依赖性 Sirt1 活性，而这些在 AAA 组织中均降低。此外，Sirt1 的药理学抑制消除了烟酰胺对 AAA 形成的保护作用。
烟酸独立于 GPR109A 保护 AAA 的形成，最有可能是作为 NAD+的前体。使用与烟酰胺相关的生物分子补充 NAD+可能是预防或治疗 AAA 的一种有效且耐受良好的方法。
