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

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without effective medications. This study integrated genetic, proteomic, and metabolomic data to identify causation between increased triglyceride (TG)-rich lipoproteins and AAA risk. Three hypertriglyceridemia mouse models were employed to test the hypothesis that increased plasma TG concentrations accelerate AAA development and rupture. In the angiotensin II-infusion AAA model, most Lpl-deficient mice with severely high plasma TG concentrations died of aortic rupture. Consistently, Apoa5-deficient mice with moderately increased TG concentrations had accelerated AAA development, while human APOC3 transgenic mice with dramatically increased TG concentrations exhibited aortic dissection and rupture. Increased TG concentrations and palmitate inhibited lysyl oxidase maturation. Locally overexpressing lysyl oxidase eliminated the impact of high TG on AAA formation in human APOC3 transgenic mice. Administration of antisense oligonucleotide targeting Angptl3 profoundly inhibited AAA progression in human APOC3 transgenic mice and Apoe-deficient mice. These results indicate that hypertriglyceridemia is a key contributor to AAA pathogenesis, highlighting the importance of triglyceride-rich lipoprotein management in treating AAA. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIThis study integrates genetic, proteomic, and metabolomic data to identify causation between increased triglyceride (TG)-rich lipoproteins and AAA risk. C_LIO_LITG concentrations influence AAA formation and severity in a dose-dependent manner, potentially by inhibiting lysyl oxidase maturation and extracellular matrix assembly. C_LIO_LIAdministration of antisense oligonucleotide targeting Angptl3 profoundly inhibites AAA progression in human APOC3 transgenic mice and Apoe-deficient mice by lowering TG concentrations. C_LI What Are the Clinical Implications?O_LIThese findings underscore triglyceride-rich lipoprotein management as a promising therapeutic strategy for AAA treatment. C_LIO_LIAntisense oligonucleotide therapy targeting liver ANGPTL3 holds potential as a therapeutic approach to reduce AAA risk. C_LI