Objective: Epidemiological studies link hyperlipidemia with increased risk for abdominal aortic aneurysms (AAAs). However, the influence of lipid-lowering drugs statins on prevalence and progression of clinical and experimental AAAs varies between reports, engendering controversy on the association of hyperlipidemia with AAA disease. This study investigated the impact of hypercholesterolemia on elastase-induced experimental AAAs in mice. Methods: Both spontaneous (targeted deletion of apolipoprotein E) and induced mouse hypercholesterolemia models were employed. In male wild type (WT) C57BL/6J mice, hypercholesterolemia was induced via intraperitoneal injection of an adeno-associated virus (AAV) encoding a gain-of-function proprotein convertase subtilisin/kexin type 9 mutation (PCSK9) followed by the administration of a high-fat diet (HFD) (PCSK9+HFD) for two weeks. As normocholesterolemic controls for PCSK9+HFD mice, WT mice were infected with PCSK9 AAV and fed normal chow, or injected with phosphate-buffered saline alone and fed HFD chow. AAAs were induced in all mice by intra-aortic infusion of porcine pancreatic elastase and assessed by ultrasonography and histopathology. Results: In spontaneous hyper- and normo-cholesterolemic male mice, the aortic diameter enlarged at a constant rate from day 3 through day 14 following elastase infusion. AAAs, defined as a more than 50% diameter increase over baseline measurements, formed in all mice. AAA progression was more pronounced in male mice, with or without spontaneous hyperlipidemia. The extent of elastin degradation and smooth muscle cell depletion were similar in spontaneous hyper- (score 3.5 for elastin and 4.0 for smooth muscle) and normo- (both scores 4.0) cholesterolemic male mice. Aortic mural macrophage accumulation was also equivalent between the two groups. No differences were observed in aortic accumulation of CD4⁺ or CD8⁺ T cells, B cells, or mural angiogenesis between male spontaneous hyper- and normocholesterolemic mice. Similarly, no influence of spontaneous hypercholesterolemia on characteristic aneurysmal histopathology was noted in female mice. In confirmatory experiments, induced hypercholesterolemia also exerted no appreciable effect on AAA progression and histopathologies. Conclusion: This study demonstrated no recognizable impact of hypercholesterolemia on elastase-induced experimental AAA progression in both spontaneous and induced hypercholesterolemia mouse models. These results add further uncertainty to the controversy surrounding the efficacy of statin therapy in clinical AAA disease.

Background: Gasdermin D, a molecule downstream of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing inflammasome, forms the membrane pore for the secretion of interleukin (IL)-1β and IL-18, and also mediates pyroptosis. This study was to explore the influence of treatment with disulfiram, a small molecule inhibitor to gasdermin D, on the formation and progression of experimental abdominal aortic aneurysms (AAA). Methods: AAAs were induced in 10-week-old male apolipoprotein E deficient mice by subcutaneous infusion of angiotensin II (1000 ng/min/kg body weight) for 28 days via osmotic minipumps. Three days prior to angiotensin II infusion, disulfiram (50 mg/kg) or an equal volume of saline as the vehicle control was administered daily via oral gavage. The influence on experimental AAAs was analyzed by serial measurements of aortic diameters via ultrasonography, grading AAA severity and histopathology at sacrifice. Serum IL-1β and IL-18 levels, systolic blood pressure, total cholesterol, and triglyceride were also measured. Additional experiments assayed the influences on the cell viability and IL-1β secretion of in vitro activated macrophages. Results: Disulfiram significantly reduced the enlargement, incidence, and severity of angiotensin II-induced experimental AAAs with attenuation of medial elastin breaks, mural macrophage accumulation, and systolic blood pressure. The AAA suppression was also associated with reduced systemic levels of IL-1β but not IL-18. However, disulfiram treatment had no impact on body weight gain and lipid levels in aneurysmal mice. Additionally, disulfiram treatment also markedly reduced the secretion of IL-1β from activated macrophages with a limited effect on cell viability in vitro. Conclusions: Gasdermin D inhibition by disulfiram attenuated angiotensin II-induced experimental AAAs with reduced systemic IL-1β levels and in vitro activated macrophage IL-1β secretion. Our study suggests that pharmacological gasdermin D inhibition may have translational potential for limiting clinical AAA progression.

Background: Although diabetes attenuates abdominal aortic aneurysms (AAAs), the mechanisms by which diabetes suppresses AAAs remain incompletely understood. Accumulation of advanced glycation end‐ (AGEs) reduces extracellular matrix (ECM) degradation in diabetes. Because ECM degradation is critical for AAA pathogenesis, we investigated whether AGEs mediate experimental AAA suppression in diabetes by blocking AGE formation or disrupting AGE‐ECM cross‐linking using small molecule inhibitors. Methods and Results: Male C57BL/6J mice were treated with streptozotocin and intra‐aortic elastase infusion to induce diabetes and experimental AAAs, respectively. Aminoguanidine (AGE formation inhibitor, 200 mg/kg), alagebrium (AGE‐ECM cross‐linking disrupter, 20 mg/kg), or vehicle was administered daily to mice from the last day following streptozotocin injection. AAAs were assessed via serial aortic diameter measurements, histopathology, and in vitro medial elastolysis assays. Treatment with aminoguanidine, not alagebrium, diminished AGEs in diabetic AAAs. Treatment with both inhibitors enhanced aortic enlargement in diabetic mice as compared with vehicle treatment. Neither enhanced AAA enlargement in nondiabetic mice. AAA enhancement in diabetic mice by aminoguanidine or alagebrium treatment promoted elastin degradation, smooth muscle cell depletion, mural macrophage accumulation, and neoangiogenesis without affecting matrix metalloproteinases, C‐C motif chemokine ligand 2, or serum glucose concentration. Additionally, treatment with both inhibitors reversed suppression of diabetic aortic medial elastolysis by porcine pancreatic elastase in vitro. Conclusions: Inhibiting AGE formation or AGE‐ECM cross‐linking enhances experimental AAAs in diabetes. These findings support the hypothesis that AGEs attenuate experimental AAAs in diabetes. These findings underscore the potential translational value of enhanced ECM cross‐linking as an inhibitory strategy for early AAA disease.

Background: Interleukin‐19 is an immunosuppressive cytokine produced by immune and nonimmune cells, but its role in abdominal aortic aneurysm (AAA) pathogenesis is not known. This study aimed to investigate interleukin‐19 expression in, and influences on, the formation and progression of experimental AAAs. Methods and Results: Human specimens were obtained at aneurysm repair surgery or from transplant donors. Experimental AAAs were created in 10‐ to 12‐week‐old male mice via intra‐aortic elastase infusion. Influence and potential mechanisms of interleukin‐19 treatment on AAAs were assessed via ultrasonography, histopathology, flow cytometry, and gene expression profiling. Immunohistochemistry revealed augmented interleukin‐19 expression in both human and experimental AAAs. In mice, interleukin‐19 treatment before AAA initiation via elastase infusion suppressed aneurysm formation and progression, with attenuation of medial elastin degradation, smooth‐muscle depletion, leukocyte infiltration, neoangiogenesis, and matrix metalloproteinase 2 and 9 expression. Initiation of interleukin‐19 treatment after AAA creation limited further aneurysmal degeneration. In additional experiments, interleukin‐19 treatment inhibited murine macrophage recruitment following intraperitoneal thioglycolate injection. In classically or alternatively activated macrophages in vitro, interleukin‐19 downregulated mRNA expression of inducible nitric oxide synthase, chemokine C‐C motif ligand 2, and metalloproteinases 2 and 9 without apparent effect on cytokine‐expressing helper or cytotoxic T‐cell differentiation, nor regulatory T cellularity, in the aneurysmal aorta or spleen of interleukin‐19–treated mice. Interleukin‐19 also suppressed AAAs created via angiotensin II infusion in hyperlipidemic mice. Conclusions: Based on human evidence and experimental modeling observations, interleukin‐19 may influence the development and progression of AAAs.