AUTHOR=Suur Bianca E. , Chemaly Melody , Lindquist Liljeqvist Moritz , Djordjevic Djordje , Stenemo Markus , Bergman Otto , Karlöf Eva , Lengquist Mariette , Odeberg Jacob , Hurt-Camejo Eva , Eriksson Per , Ketelhuth Daniel F.J. , Roy Joy , Hedin Ulf , Nyberg Michael , Matic Ljubica 

TITLE=Therapeutic potential of the Proprotein Convertase Subtilisin/Kexin family in vascular disease

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.988561

DOI=10.3389/fphar.2022.988561

ISSN=1663-9812

ABSTRACT=<p>Proprotein convertase subtilisin/kexins (PCSKs) constitute a family of nine related proteases: PCSK1-7, MBTPS1, and PCSK9. Apart from PCSK9, little is known about PCSKs in cardiovascular disease. Here, we aimed to investigate the expression landscape and druggability potential of the entire PCSK family for CVD. We applied an integrative approach, combining genetic, transcriptomic and proteomic data from three vascular biobanks comprising carotid atherosclerosis, thoracic and abdominal aneurysms, with patient clinical parameters and immunohistochemistry of vascular biopsies. Apart from <italic>PCSK4</italic>, all PCSK family members lie in genetic regions containing variants associated with human cardiovascular traits. Transcriptomic analyses revealed that <italic>FURIN</italic>, <italic>PCSK5, MBTPS1</italic> were downregulated, while <italic>PCSK6/7</italic> were upregulated in plaques vs. control arteries. In abdominal aneurysms, <italic>FURIN, PCSK5</italic>, <italic>PCSK7</italic>, <italic>MBTPS1</italic> were downregulated, while <italic>PCSK6</italic> was enriched in diseased media. In thoracic aneurysms, only <italic>FURIN</italic> was significantly upregulated. Network analyses of the upstream and downstream pathways related to PCSKs were performed on the omics data from vascular biopsies, revealing mechanistic relationships between this protein family and disease. Cell type correlation analyses and immunohistochemistry showed that PCSK transcripts and protein levels parallel each other, except for PCSK9 where transcript was not detected, while protein was abundant in vascular biopsies. Correlations to clinical parameters revealed a positive association between <italic>FURIN</italic> plaque levels and serum LDL, while <italic>PCSK6</italic> was negatively associated with Hb. <italic>PCSK5/6/7</italic> were all positively associated with adverse cardiovascular events. Our results show that <italic>PCSK6</italic> is abundant in plaques and abdominal aneurysms, while <italic>FURIN</italic> upregulation is characteristic for thoracic aneurysms. PCSK9 protein, but not the transcript, was present in vascular lesions, suggesting its accumulation from circulation. Integrating our results lead to the development of a novel ‘molecular’ 5D framework. Here, we conducted the first integrative study of the proprotein convertase family in this context. Our results using this translational pipeline, revealed primarily PCSK6, followed by PCSK5, PCSK7 and FURIN, as proprotein convertases with the highest novel therapeutic potential.</p>