Abstract Body: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without effective medications. This study integrated genetic, proteomic, and metabolomic data to identify that increased triglyceride-rich lipoproteins (TRL) accelerate AAA development and rupture, and modulating triglyceride (TG) concentrations may become new therapeutic strategies for AAA. Three hypertriglyceridemia mouse models were employed to test the hypothesis that increased plasma TG concentrations accelerate AAA development and rupture. To minimize the effects of hypercholesterolemia induced by a Western diet on AAA development, the animals used in this study were placed on a standard rodent laboratory diet. In the angiotensin II-infusion AAA model, Apoa5-deficient mice with moderately increased TG concentrations with no difference in total cholesterol (TC) concentrations had accelerated AAA development. Compared with controls, male hAPOC3 transgenic (Tg) mice had about 7-fold increase in plasma TG concentrations and about 1-fold elevations in plasma TC concentrations. There was a dramatically increased AAA incidence, a larger maximal diameter of the suprarenal aorta in hAPOC3 Tg mice (11 out of 13 surviving animals), and a higher dissection rate. To explore whether lowering TG levels could attenuate AAA formation and rupture, we administrated antisense nucleotides (ASO) targeting angiopoietin-like protein-3 (Angptl3) and found that Angptl3 ASO protected against hypertriglyceridemia accelerated AAA development in hAPOC3 Tg mice. Furthermore, administration of Angptl3 ASO inhibited AAA development in Apoe-deficient mice, with significantly decreased TG concentrations by 50% and slightly reduced TC concentrations by 8% when placed on a standard rodent laboratory diet. These results indicate that increased TG-rich lipoproteins accelerate AAA formation and rupture and also provide evidence that effective management of plasma TG concentrations can alleviate AAA progression.