The role of Proprotein Convertase Subtilisins Kexins (PCSKs) in vascular disease
Vascular diseases comprise conditions like atherosclerosis, aortic aneurysms and restenosis after surgical interventions, contributing to high overall cardiovascular mortality. Pathological vessel changes are generally featured by inflammatory, degenerative but also regenerative processes involving lipids, immune and smooth muscle cells (SMCs). Given the capacity of SMCs to provide tissue integrity, we hypothesize that understanding of mechanisms that regulate their function can yield new strategies to prevent vascular complications. By molecular profiling of human atherosclerotic plaques, we previously revealed that proprotein convertase PCSK6 is one of the most enriched molecules in unstable vs. stable atherosclerosis patients, localized in SMCs. Subsequent investigations in PCSK6-/- mice, animal vascular injury models, ex vivo and in vitro, identified a functional link between increased PCSK6, vascular remodeling and SMC migration in vascular injury and disease. The PCSK class comprises 9 enzymes which have been poorly studied in vascular disease, apart from PCSK9 that regulates LDL metabolism and is a major lipid-lowering therapeutic target. We are currently conducting a comprehensive exploration of the PCSK-dependent mechanisms in vascular disease, utilizing an integrative systems approach with deep profiling from several independent human cardiovascular cohorts and experimental studies. Candidates with translational potential will be further evaluated as biomarkers, therapeutics or for targeted molecular diagnostics, to improve risk-stratification of patients with vascular disease.