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