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

Abstract

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. 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. 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. 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.