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

Abstract

AbstractAbdominal 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, mostLpl-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 humanAPOC3transgenic mice with dramatically increased TG concentrations exhibited aortic dissection and rupture. Increased TG concentrations and palmitate inhibited lysyl oxidase maturation. Administration of antisense oligonucleotide targetingAngptl3profoundly inhibited AAA progression in humanAPOC3transgenic mice andApoe-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.