Inhibition of ATP-citrate lyase by bempedoic acid protects against abdominal aortic aneurysm formation in mice.

Abstract

Abdominal aortic aneurysm (AAA) is a prevalent degenerative disease characterized by an exacerbated inflammation and destructive vascular remodeling. Unfortunately, effective pharmacological tools for the treatment of this disease remain a challenge. ATP-citrate lyase (ACLY), the primary enzyme responsible for acetyl-CoA biosynthesis, is a key regulator of inflammatory signaling in macrophages and lymphocytes. Here, we found increased levels of the active (phosphorylated) form of ACLY (p-ACLY) in the inflammatory infiltrate of AAA from patients and in aneurysmal lesions from angiotensin II (Ang II)-infused apolipoprotein E-deficient mice (ApoE^-/-). Furthermore, plasma ACLY levels positively correlates with IL6 and IFNγ levels in patients with AAA, while inflammatory stimuli strongly upregulated ACLY expression in macrophages and Jurkat cells. The administration of the ACLY inhibitor bempedoic acid (BemA) protected against Ang II-induced AAA formation in ApoE^-/- mice, limiting the progression of aortic dilatation and reducing mortality due to aortic rupture. BMS-303141, another ACLY inhibitor, also ameliorated AAA formation, although to a lesser extent. BemA attenuated vascular remodeling and the disorganization and rupture of elastic fibers induced by Ang II, as well as vascular inflammation, decreasing the recruitment of macrophages (CD68 +) and neutrophils (Ly-6G+) into the aortic wall. Moreover, BemA shifted splenic monocytes toward a functionally anti-inflammatory phenotype, and increased the percentage of CD4⁺CD69⁺ cells. Taken together, these results support the contribution of ACLY to AAA and point to BemA as a promising tool to be considered for future clinical trials addressing the management of this disease which is quite often associated with disorders of lipoprotein metabolism.