title: The Proprotein Convertases in Hypercholesterolemia and Cardiovascular Diseases: Emphasis on Proprotein Convertase Subtilisin/Kexin 9.
abstract: The secretory proprotein convertase (PC) family comprises nine members, as follows: PC1/3, PC2, furin, PC4, PC5/6, paired basic amino acid cleaving enzyme 4, PC7, subtilisin kexin isozyme 1/site 1 protease (SKI-1/S1P), and PC subtilisin/kexin type 9 (PCSK9). The first seven PCs cleave their substrates at single/paired basic residues and exhibit specific and often essential functions during development and/or in adulthood. The essential SKI-1/S1P cleaves membrane-bound transcription factors at nonbasic residues. In contrast, PCSK9 cleaves itself once, and the secreted inactive protease drags the low-density lipoprotein receptors (LDLR) and very LDLR (VLDLR) to endosomal/lysosomal degradation. Inhibitory PCSK9 monoclonal antibodies are now prescribed to treat hypercholesterolemia. This review focuses on the implication of PCs in cardiovascular functions and diseases, with a major emphasis on PCSK9. We present a phylogeny of the PCs and the analysis of PCSK9 haplotypes in modern and archaic human species. The absence of PCSK9 in mice led to the discovery of a sex- and tissue-specific subcellular distribution of the LDLR and VLDLR. PCSK9 inhibition may have other applications because it reduces inflammation and sepsis in a LDLR-dependent manner. Our present understanding of the cellular mechanism(s) that enables PCSK9 to induce the degradation of receptors is reviewed, as well as the consequences of its key natural mutations. The PCSK9 ongoing clinical trials are reviewed. Finally, how the other PCs may impact cardiovascular disease and the metabolic syndrome, and become relevant targets, is discussed.
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, affiliated to Université de Montréal, QC, Canada (N.G.S., A.P.); LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris, France (M.A., C.B.); Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie-Santé, Saint-Joseph University, Beirut, Lebanon (M.A.); Department of Integrative Biology, Center for Theoretical Evolutionary Genomics, University of California Berkeley, Berkeley, California (S.P.); Department of Biology, Stanford University, Stanford, California (S.P.); and Département de Génétique, AP-HP, CHU Xavier Bichat, and Université Paris Diderot, Paris, France (C.B.) seidahn@ircm.qc.ca.
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, affiliated to Université de Montréal, QC, Canada (N.G.S., A.P.); LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris, France (M.A., C.B.); Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie-Santé, Saint-Joseph University, Beirut, Lebanon (M.A.); Department of Integrative Biology, Center for Theoretical Evolutionary Genomics, University of California Berkeley, Berkeley, California (S.P.); Department of Biology, Stanford University, Stanford, California (S.P.); and Département de Génétique, AP-HP, CHU Xavier Bichat, and Université Paris Diderot, Paris, France (C.B.).
authors.forename: Marianne
authors.initials: M
authors.lastname: Abifadel
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, affiliated to Université de Montréal, QC, Canada (N.G.S., A.P.); LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris, France (M.A., C.B.); Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie-Santé, Saint-Joseph University, Beirut, Lebanon (M.A.); Department of Integrative Biology, Center for Theoretical Evolutionary Genomics, University of California Berkeley, Berkeley, California (S.P.); Department of Biology, Stanford University, Stanford, California (S.P.); and Département de Génétique, AP-HP, CHU Xavier Bichat, and Université Paris Diderot, Paris, France (C.B.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Prost
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, affiliated to Université de Montréal, QC, Canada (N.G.S., A.P.); LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris, France (M.A., C.B.); Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie-Santé, Saint-Joseph University, Beirut, Lebanon (M.A.); Department of Integrative Biology, Center for Theoretical Evolutionary Genomics, University of California Berkeley, Berkeley, California (S.P.); Department of Biology, Stanford University, Stanford, California (S.P.); and Département de Génétique, AP-HP, CHU Xavier Bichat, and Université Paris Diderot, Paris, France (C.B.).
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, affiliated to Université de Montréal, QC, Canada (N.G.S., A.P.); LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris, France (M.A., C.B.); Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie-Santé, Saint-Joseph University, Beirut, Lebanon (M.A.); Department of Integrative Biology, Center for Theoretical Evolutionary Genomics, University of California Berkeley, Berkeley, California (S.P.); Department of Biology, Stanford University, Stanford, California (S.P.); and Département de Génétique, AP-HP, CHU Xavier Bichat, and Université Paris Diderot, Paris, France (C.B.).
authors.forename: Annik
authors.initials: A
authors.lastname: Prat
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D002784:Cholesterol / Q000097:blood*; D005260:Female; D006239:Haplotypes; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000201:enzymology*; D017270:Lipoprotein(a) / Q000097:blood; D008297:Male; D009154:Mutation; D000091362:PCSK9 Inhibitors; D010802:Phylogeny; D000071449:Proprotein Convertase 9 / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D011973:Receptors, LDL / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use
chemical_list: D000924:Anticholesteremic Agents; D015415:Biomarkers; C573412:LDLR protein, human; D017270:Lipoprotein(a); D000091362:PCSK9 Inhibitors; D011973:Receptors, LDL; D015842:Serine Proteinase Inhibitors; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9