Hypertriglyceridemia as a Key Contributor to Abdominal Aortic Aneurysm Development and Rupture: Insights From Genetic and Experimental Models.

IF 38.6 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Circulation Pub Date : 2025-09-23 Epub Date: 2025-08-05 DOI:10.1161/CIRCULATIONAHA.125.074737
Yaozhong Liu, Huilun Wang, Minzhi Yu, Lei Cai, Ying Zhao, Yalun Cheng, Yongjie Deng, Yang Zhao, Haocheng Lu, Xiaokang Wu, Guizhen Zhao, Chao Xue, Hongyu Liu, Ida Surakka, Anna Schwendeman, Hong S Lu, Alan Daugherty, Lin Chang, Jifeng Zhang, Ryan E Temel, Y Eugene Chen, Yanhong Guo
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引用次数: 0

Abstract

Background: 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.

Methods: 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 Lpl-deficient, Apoa5-deficient, and human APOC3 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 mediator in the suprarenal abdominal aorta. Antisense oligonucleotides targeting Angptl3 were administered to reduce TG levels and assess therapeutic potential in human APOC3 transgenic and Apoe-deficient mice.

Results: Mendelian randomization analyses integrating genetic, proteomic, and metabolomic data identified causal relationships between elevated TG-rich lipoproteins, TG metabolism-related proteins/metabolites, and AAA risk. In the angiotensin II infusion AAA model, most Lpl-deficient mice with severely elevated TG concentrations died of aortic rupture. Similarly, Apoa5-deficient mice with moderately elevated TG levels developed accelerated AAA, and human APOC3 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 APOC3 transgenic mice. Moreover, an Angptl3-targeting antisense oligonucleotide profoundly attenuated AAA progression in both human APOC3 transgenic and Apoe-deficient mice.

Conclusions: 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.

高甘油三酯血症是腹主动脉瘤发展和破裂的关键因素:来自遗传和实验模型的见解。
背景: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发展中的因果作用仍然不清楚和有争议。方法: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水平升高加速AAA发展的假设,我们使用了表现出不同程度高甘油三酯血症的lpl缺陷、apoa5缺陷和人类APOC3转基因小鼠。通过棕榈酸处理血管平滑肌细胞的RNA测序和Western blot分析进行了机制研究,并通过在肾上腹主动脉局部过表达关键介质进行了体内验证。针对Angptl3的反义寡核苷酸被用于降低人APOC3转基因和apoe缺陷小鼠的TG水平并评估其治疗潜力。结果:孟德尔随机分析整合了遗传、蛋白质组学和代谢组学数据,确定了富含TG的脂蛋白、TG代谢相关蛋白/代谢物升高与AAA风险之间的因果关系。在血管紧张素II输注AAA模型中,大多数lpl缺陷小鼠,TG浓度严重升高,死于主动脉破裂。同样,apoa5缺陷小鼠,TG水平适度升高,发生AAA加速,人APOC3转基因小鼠,TG水平急剧升高,发生主动脉夹层和破裂。从机制上说,TG和棕榈酸酯的升高抑制了赖氨酸氧化酶(LOX)的成熟并降低了LOX的活性。在人apo3转基因小鼠中,局部过表达赖氨酸氧化酶消除了高甘油三酯血症的原动脉瘤效应。此外,一种靶向angptl3的反义寡核苷酸在人APOC3转基因小鼠和apoe缺陷小鼠中都能显著减弱AAA的进展。结论:这些发现确定了高甘油三酯血症是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希望的AAA治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Circulation
Circulation 医学-外周血管病
CiteScore
45.70
自引率
2.10%
发文量
1473
审稿时长
2 months
期刊介绍: Circulation is a platform that publishes a diverse range of content related to cardiovascular health and disease. This includes original research manuscripts, review articles, and other contributions spanning observational studies, clinical trials, epidemiology, health services, outcomes studies, and advancements in basic and translational research. The journal serves as a vital resource for professionals and researchers in the field of cardiovascular health, providing a comprehensive platform for disseminating knowledge and fostering advancements in the understanding and management of cardiovascular issues.
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