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

Yaozhong Liu, Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Huilun Wang, Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Minzhi Yu, Department of Pharmacology, University of Michigan, Ann Arbor.
Lei Cai, Saha Cardiovascular Research Center and Department of Physiology, College of Medicine, University of Kentucky, Lexington.
Ying Zhao, Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Yalun Cheng, Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Yongjie Deng, Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Yang Zhao, Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Haocheng Lu, Department of Pharmacology, Southern University of Science and Technology, Guangdong, China.
Xiaokang Wu, Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Guizhen Zhao, Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Chao Xue, Rochester Regional HealthFollow
Hongyu Liu, Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Ida Surakka, Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Anna Schwendeman, Department of Pharmacology, University of Michigan, Ann Arbor.
Hong S. Lu, Saha Cardiovascular Research Center and Department of Physiology, College of Medicine, University of Kentucky, Lexington.
Alan Daugherty, Saha Cardiovascular Research Center and Department of Physiology, College of Medicine, University of Kentucky, Lexington.
Lin Chang, Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Jifeng Zhang, Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Ryan E. Temel, Saha Cardiovascular Research Center and Department of Physiology, College of Medicine, University of Kentucky, Lexington.
Y Eugene Chen, Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Yanhong Guo, Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.

Department

Internal Medicine

Document Type

Article

Publication Title

Circulation

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.

First Page

862

Last Page

881

DOI

10.1161/CIRCULATIONAHA.125.074737

Volume

152

Issue

12

Publication Date

9-23-2025

Medical Subject Headings

Animals; Aortic Aneurysm, Abdominal (genetics, etiology, pathology, blood, metabolism); Hypertriglyceridemia (genetics, complications, blood); Apolipoprotein C-III (genetics, metabolism); Humans; Mice; Disease Models, Animal; Mice, Transgenic; Aortic Rupture (genetics, etiology, blood, pathology, metabolism); Lipoprotein Lipase (genetics, deficiency); Apolipoprotein A-V (genetics, deficiency); Triglycerides (blood); Male; Angiopoietin-Like Protein 3; Mice, Inbred C57BL; Angiopoietin-like Proteins (genetics, metabolism); Mice, Knockout; Mice, Knockout, ApoE; Mendelian Randomization Analysis

PubMed ID

40762097

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