Bempedoic acid attenuates vascular inflammation and oxidative stress in a preclinical model of abdominal aortic aneurysm.

Abstract

Background: Inflammation, oxidative stress, and vascular remodeling play a key role in the pathophysiology of abdominal aortic aneurysm (AAA), a severe vascular disease. Previously, we had demonstrated an increase in the phosphorylated form of ATP citrate lyase (p-ACLY) in AAA and that bempedoic acid (BemA), a specific inhibitor of this enzyme, attenuates aneurysm formation in an experimental model. In this study, we further investigated the mechanisms mediating the beneficial effect of BemA.

Methods: AAA was induced by angiotensin II (AngII) infusion in ApoE^-/- mice, and aneurysm formation was assessed by ultrasonography. Histological analyses (hematoxylin-eosin, orcein staining) and immunohistochemistry were performed. T cell subpopulations in the spleen were characterized by flow cytometry, and superoxide anion production in the vascular wall was evaluated by dihydroethidium (DHE) staining. The expression of enzymes involved in the control of oxidative stress was analyzed by real-time RT-PCR.

Results: Endpoint ultrasonography analyses in AngII-infused ApoE^-/- mice confirmed that BemA limits aneurysm formation. Indeed, BemA administration in AngII-infused mice significantly increased both the percentage of animals that did not develop aneurysms and those free of aortic rupture, without altering the pressor effect of AngII. Histologically, BemA preserved the integrity of the aortic wall and reduced the proportion of animals presenting intramural thrombi, with a decrease in hematoma area. Immunohistochemical analyses showed increased levels of p-ACLY in the inflammatory infiltrate of human and murine aneurysmal lesions, as well as BemA's capacity to attenuate the AngII-induced increase in CD3⁺ T lymphocyte content in the vascular wall. Additionally, analysis of splenic CD8⁺ T cell subpopulations revealed no significant changes in either AngII-infused animals or those treated with BemA. Finally, ACLY activity inhibition decreased reactive oxygen species production without modifying the expression of key isoforms of the NADPH oxidase (Nox2, Nox4) or superoxide dismutase (Sod1, Sod2) families.

Conclusions: Taken together, these findings position ACLY as a relevant therapeutic target in AAA and BemA as a drug with potential protective effects against the development and progression of this vascular disease.