Liu Yaozhong, Wang Huilun, Yu Minzhi, Cai Lei, Zhao Ying, Cheng Yalun, Deng Yongjie, Zhao Yang, Lu Haocheng, Wu Xiaokang, Zhao Guizhen, Xue Chao, Liu Hongyu, Surakka Ida, Schwendeman Anna, Lu Hong S, Daugherty Alan, Chang Lin, Zhang Jifeng, Temel Ryan E, Chen Y Eugene, Guo Yanhong
Frankel Cardiovascular Center, Department of Internal Medicine (Y.L., H.W., Ying Zhao, Y.C., Y.D., Yang Zhao, X.W., G.Z., C.X., H. Liu, I.S., L.C., J.Z., Y.E.C., Y.G.), University of Michigan Medical Center, Ann Arbor.
Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville (H.W.).
Circulation. 2025 Aug 5. doi: 10.1161/CIRCULATIONAHA.125.074737.
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease with no effective pharmacological treatments. The causal role of triglycerides (TGs) in AAA development remains unclear and controversial.
Mendelian randomization was applied to assess causal relationships between lipoproteins, circulating proteins, metabolites, and the risk of AAA. To test the hypothesis that elevated plasma TG levels accelerate AAA development, we used -deficient, -deficient, and human transgenic mice, which display varying degrees of hypertriglyceridemia. Mechanistic studies were performed using RNA sequencing and Western blot analysis of palmitate-treated vascular smooth muscle cells and validated in vivo by local overexpression of key mediators in the suprarenal abdominal aorta. Antisense oligonucleotides targeting were administered to reduce TG levels and assess therapeutic potential in human transgenic and -deficient mice.
Mendelian randomization analyses integrating genetic, proteomic, and metabolomic data identified a causal relationship between elevated TG-rich lipoproteins, TG metabolism-related proteins/metabolites, and AAA risk. In the angiotensin II infusion AAA model, most -deficient mice with severely elevated TG concentrations died of aortic rupture. Similarly, -deficient mice with moderately elevated TG levels developed accelerated AAA, and human transgenic mice with dramatically elevated TG levels exhibited aortic dissection and rupture. Mechanistically, elevated TG and palmitate inhibited lysyl oxidase (LOX) maturation and reduced LOX activity. Locally overexpressing lysyl oxidase eliminated the proaneurysmal effect of hypertriglyceridemia in human transgenic mice. Moreover, an -targeting antisense oligonucleotide profoundly attenuated AAA progression in both human transgenic and -deficient mice.
These findings identify hypertriglyceridemia as a key contributor to AAA pathogenesis and suggest that targeting TG-rich lipoproteins may be a promising therapeutic strategy for AAA.
腹主动脉瘤（AAA）是一种危及生命的血管疾病，目前尚无有效的药物治疗方法。甘油三酯（TGs）在AAA发生发展中的因果作用仍不明确且存在争议。
采用孟德尔随机化方法评估脂蛋白、循环蛋白、代谢物与AAA风险之间的因果关系。为了验证血浆TG水平升高会加速AAA发展这一假设，我们使用了apoE基因缺陷、Ldlr基因缺陷以及人载脂蛋白转基因小鼠，这些小鼠表现出不同程度的高甘油三酯血症。通过对棕榈酸处理的血管平滑肌细胞进行RNA测序和蛋白质印迹分析开展机制研究，并通过在肾上腹主动脉局部过表达关键介质在体内进行验证。给予靶向apoB的反义寡核苷酸以降低TG水平，并评估其在人载脂蛋白转基因小鼠和Ldlr基因缺陷小鼠中的治疗潜力。
整合遗传、蛋白质组学和代谢组学数据的孟德尔随机化分析确定了富含TG的脂蛋白升高、TG代谢相关蛋白/代谢物与AAA风险之间的因果关系。在血管紧张素II输注诱导的AAA模型中，大多数TG浓度严重升高的apoE基因缺陷小鼠死于主动脉破裂。同样，TG水平中度升高的Ldlr基因缺陷小鼠AAA发展加速，而TG水平显著升高的人载脂蛋白转基因小鼠出现主动脉夹层和破裂。机制上，TG和棕榈酸水平升高会抑制赖氨酰氧化酶（LOX）成熟并降低LOX活性。在人载脂蛋白转基因小鼠中局部过表达赖氨酰氧化酶消除了高甘油三酯血症的促动脉瘤效应。此外，一种靶向apoB的反义寡核苷酸显著减轻了人载脂蛋白转基因小鼠和Ldlr基因缺陷小鼠的AAA进展。
这些发现表明高甘油三酯血症是AAA发病机制的关键因素，并提示靶向富含TG的脂蛋白可能是一种有前景的AAA治疗策略。
