Pcsk6 Ablation In Vascular Smooth Muscle Cells Promotes Abdominal Aortic Aneurysm Development And Rupture

Background and Aim: We have previously shown that Proprotein Convertase Subtilisin/Kexin type 6 (Pcsk6) is strongly enriched in atherosclerotic plaques and plays a key role in lesion vulnerability and vessel wall healing by regulating vascular smooth muscle cell (VSMC) migration, proliferation, and extracellular matrix remodeling. Considering the broad importance of these processes in vascular pathologies, this study aimed to investigate the expression and function of Pcsk6 in the abdominal aortic aneurysm (AAA). Methods and Results: Bioinformatic analysis of human transcriptome microarray and RNA-sequencing data from human AAA biobanks of the Karolinska Institute and the Technical University of Munich have demonstrated a significantly increased level of Pcsk6 transcript in AAA tissues compared to controls, and even higher levels in ruptured AAAs. Single-cell RNA sequencing data demonstrated a significantly increased level of Pcsk6 transcript in fibroblasts and T cells but decreased in VSMCs. To further clarify if Pcsk6 dysregulation in VSMCs is a pathological reaction or if it has a causal role in AAA development and aortic dissection, we performed pilot animal studies: 1) peri-adventitial porcine pancreatic elastase (PPE) induced AAA model on male VSMC conditional Tagln-Pcsk6 deficient and control mice; 2) AngII infusion model on male Tagln-Pcsk6 deficient and control mice with ApoE-/- background. Interestingly, although no difference in baseline blood pressure, aortic dilatation, and constriction was found between Tagln-Pcsk6 deficient and control mice, ultrasound imaging and histology analyses showed that mice with Pcsk6 deficiency in VSMCs manifested remarkably larger AAA, as well as significantly increased rupture and dissection rate. Mechanistically, RNA sequencing analysis indicated significant inhibition of extracellular matrix components and biosynthesis signaling in aortas from Tagln-Pcsk6 deficient mice. Conclusion: PCSK6 expressed by VSMCs plays a substantial role in AAA progression and aortic dissection, opening new avenues for the therapy of aortic disease. Further mechanistic studies are necessary before this translational aspect can be evaluated.