Abstract 13662: The Role of Pcsk9 in Abdominal Aortic Aneurysm

Abstract

Introduction: Abdominal aortic aneurysm (AAA) is a local weakening and dilatation of the abdominal aorta ≥50%, is associated with high mortality in the event of rupture and has no current pharmacologic treatment. Proprotein convertase subtilisin/kexin type 9 (Pcsk9), an enzyme mainly known for its production in liver, can cause familial hypercholesterolemia due to gain-of-function mutations. When triggered by pro-inflammatory stimuli, Pcsk9 expression by vascular smooth muscle cells (VSMC) has been found to induce cellular polyploidy, senescence, and apoptosis, hallmarks of AAA. Further, our collaborative consortium identified a relationship between Pcsk9 variants and AAA disease in humans utilizing a genome-wide association stud y (GWAS) in the Million Veteran Program. Lastly, our transcriptional profiling experiments in the porcine pancreatic elastase (PPE) model of murine AAA found significant early (Day 3) upregulation of the Pcsk9 gene in aorta.Monoclonal Pcsk9 antibody therapies are effective for hypercholesterolemic patients who are resistant to conventional statin therapy. However, the role of Pcsk9 in AAA has not been explored in depth. If Pcsk9 were found to be pivotal in disease, Pcsk9-inhibitors could be high priority candidates for investigation in limiting AAA. Methods: Using the PPE model, AAA was induced in wildtype C57Bl/6 mice and Pcsk9 knock-out (KO) mice. Aneurysm growth was monitored via sonography at various time points, and local vascular Pcsk9 and inflammatory marker gene expression were measured by qPCR. In vitro, VSMC were treated with exogenous Pcsk9 and assayed for pro-inflammatory marker expression. Results: Sonographic imaging data showed smaller AAA diameters in Pcsk9 KO mice compared with wildtype C57Bl/6 mice. Inflammatory gene expression was significantly downregulated with Pcsk9 KO. In-vitro VSMCs showed upregulated inflammation after exogenous Pcsk9 treatment. Conclusions: Our data suggest that Pcsk9 plays a crucial role in the development of AAA and could be a viable treatment target to inhibit AAA progression.