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
{"title":"Hypertriglyceridemia as a Key Contributor to Abdominal Aortic Aneurysm Development and Rupture: Insights From Genetic and Experimental Models.","authors":"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","doi":"10.1161/CIRCULATIONAHA.125.074737","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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 <i>Lpl</i>-deficient, <i>Apoa5</i>-deficient, and human <i>APOC3</i> 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 <i>Angptl3</i> were administered to reduce TG levels and assess therapeutic potential in human <i>APOC3</i> transgenic and <i>Apoe</i>-deficient mice.</p><p><strong>Results: </strong>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 <i>Lpl</i>-deficient mice with severely elevated TG concentrations died of aortic rupture. Similarly, <i>Apoa5</i>-deficient mice with moderately elevated TG levels developed accelerated AAA, and human <i>APOC3</i> 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 <i>APOC3</i> transgenic mice. Moreover, an <i>Angptl3</i>-targeting antisense oligonucleotide profoundly attenuated AAA progression in both human <i>APOC3</i> transgenic and <i>Apoe</i>-deficient mice.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"862-881"},"PeriodicalIF":38.6000,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12327802/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCULATIONAHA.125.074737","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/5 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
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.
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.