Mitochondrial NAD+ deficiency in vascular smooth muscle impairs collagen III turnover to trigger thoracic and abdominal aortic aneurysm

Thoracic and abdominal aortic aneurysm poses a substantial mortality risk in adults, yet many of its underlying factors remain unidentified. Here, we identify mitochondrial nicotinamide adenine dinucleotide (NAD)⁺ deficiency as a causal factor for the development of aortic aneurysm. Multiomics analysis of 150 surgical aortic specimens indicated impaired NAD+ salvage and mitochondrial transport in human thoracic aortic aneurysm, with expression of the NAD+ transporter SLC25A51 inversely correlating with disease severity and postoperative progression. Genome-wide gene-based association analysis further linked low SLC25A51 expression to risk of aortic aneurysm and dissection. In mouse models, smooth muscle-specific knockout of Nampt, Nmnat1, Nmnat3, Slc25a51, Nadk2 and Aldh18a1, genes involved in NAD+ salvage and transport, induced aortic aneurysm, with Slc25a51 deletion producing the most severe effects. Using these models, we suggest a mechanism that may explain the disease pathogenesis: the production of type III procollagen during aortic medial matrix turnover imposes a high demand for proline, an essential amino acid component of collagen. Deficiency in the mitochondrial NAD⁺ pool, regulated by NAD⁺ salvage and transport, hinders proline biosynthesis in mitochondria, contributing to thoracic and abdominal aortic aneurysm. Comparative gene expression profiling analysis of RNA-seq data between 32 surgically resected thoracic aorta tissues from patients who underwent aorta replacement surgery and 11 nondiseased aorta from age-matched patients who underwent coronary artery bypass surgery or heart transplant donors without aortic aneurysm, dissection, coarctation, or previous aortic repair.

胸主动脉瘤与腹主动脉瘤对成人具有极高的死亡风险，但其诸多潜在致病因素仍未明确。本研究鉴定出线粒体烟酰胺腺嘌呤二核苷酸（nicotinamide adenine dinucleotide, NAD+）缺乏是主动脉瘤发生的致病因素。对150份手术获取的主动脉标本进行多组学分析后发现，人类胸主动脉瘤中存在NAD+补救合成途径与线粒体转运功能受损的情况，且NAD+转运蛋白SLC25A51的表达水平与疾病严重程度及术后进展呈负相关。全基因组基因关联分析进一步证实，SLC25A51低表达与主动脉瘤及主动脉夹层的发病风险相关。在小鼠模型中，对参与NAD+补救合成与转运的基因Nampt、Nmnat1、Nmnat3、Slc25a51、Nadk2及Aldh18a1进行平滑肌细胞特异性敲除，均可诱导主动脉瘤发生，其中Slc25a51敲除所致病变最为严重。借助上述模型，我们提出了可解释该疾病发病机制的假说：主动脉中层基质重塑过程中III型前胶原的合成对脯氨酸（胶原蛋白的必需氨基酸组分）存在极高需求。由NAD+补救合成与转运途径调控的线粒体NAD+池缺乏，会抑制线粒体中脯氨酸的生物合成，进而促成胸主动脉瘤与腹主动脉瘤的发生。本研究对两组样本的RNA测序数据进行了比较基因表达谱分析：一组为32份接受主动脉置换手术患者的手术切除胸主动脉组织，另一组为11份年龄匹配的、无主动脉瘤、主动脉夹层、主动脉缩窄或既往主动脉修复史的冠状动脉旁路移植术患者或心脏移植供体的正常主动脉组织。