Abstract 419: Therapeutic Potential Of The Proprotein Convertase Subtilisin/Kexin (PCSK) Family In Vascular Disease

Introduction: Proprotein convertase subtilisin/kexins (PCSKs) constitute a family of 7 related proteases (PCSK1-7) and 2 distant ones (MBTPS1, PCSK9), with unexplored role in cardiovascular disease (CVD), apart from PCSK9 in lipid metabolism. Here, we aimed to investigate the expression landscape and therapeutic targeting potential of the entire PCSK family for ameliorating CVD. Methods: An integrative approach was applied with genetic, transcriptomic and proteomic data mining from public databases and three independent vascular biobanks comprising carotid atherosclerosis, thoracic and abdominal aneurysms. Omics analyses were followed by gene expression association with patient clinical parameters and immunohistochemistry in vascular biopsies. Results: Genetic studies revealed that, apart from PCSK4 , all PCSK family members lie in regions containing variants associated with human cardiovascular traits. Transcriptomic analyses showed that FURIN, PCSK5, MBTPS1 were downregulated, while PCSK6/7 were upregulated in atherosclerotic plaques vs. normal arteries. In abdominal aneurysms, FURIN, PCSK5, PCSK7, MBTPS1 were downregulated, while PCSK6 was enriched in diseased media. In thoracic aneurysms, only FURIN was significantly upregulated. To understand the mechanistic relationships of this protein family with the disease, network analyses of the upstream and downstream pathways related to PCSKs were done on the omics data from vascular biopsies. Immunohistochemistry indicated that PCSK protein levels correspond to the mRNA expression, except in the case of PCSK9 protein that was abundant in vascular biopsies. Correlation to clinical parameters in a carotid endarterectomy cohort revealed positive associations for PCSK5/6/7 with adverse cardiovascular events. Conclusions: Our results show that PCSK6 is the most enriched PCSK in plaques and abdominal aneurysms, while FURIN upregulation is characteristic for thoracic aneurysms. PCSK9 protein but not the transcript, was present in vascular lesions, suggesting its accumulation from circulation. Overall evaluation revealed that PCSK6 is the most attractive protease from this family to target for drug development in CVD.