PCSK9 deficiency reduces atherosclerosis, apolipoprotein B secretion, and endothelial dysfunction

Proprotein convertase subtilisin/kexin type 9 (PCSK9) interacts directly with cytoplasmic apoB and prevents its degradation via the autophagosome/lysosome pathway. This process affects VLDL and LDL production and influences atherogenesis. Here, we investigated the molecular machinery by which PCSK9 modulates autophagy and affects atherogenesis. We backcrossed Pcsk9−/− mice with atherosclerosis-prone Ldlr−/−Apobec1−/− (LDb) mice to generate Ldlr−/−Apobec1−/−Pcsk9−/− (LTp) mice. Deletion of PCSK9 resulted in decreased hepatic apoB secretion, increased autophagic flux, and decreased plasma levels of IDL and LDL particles. The LDLs from LTp mice (LTp-LDLs) were less atherogenic and contained less cholesteryl ester and phospholipids than LDb-LDLs. Moreover LTp-LDLs induced lower endothelial expression of the genes encoding TLR2, Lox-1, ICAM-1, CCL2, CCL7, IL-6, IL-1β, Beclin-1, p62, and TRAF6. Collectively, these effects were associated with substantially less atherosclerosis development (>4-fold) in LTp mice. The absence of PCSK9 in LDb mice results in decreased lipid and apoB levels, fewer atherogenic LDLs, and marked reduction of atherosclerosis. The effect on atherogenesis may be mediated in part by the effects of modified LDLs on endothelial cell receptors and proinflammatory and autophagy molecules. These findings suggest that there may be clinical benefits of PCSK9 inhibition due to mechanisms unrelated to increased LDL receptor activity. Proprotein convertase subtilisin/kexin type 9 (PCSK9) interacts directly with cytoplasmic apoB and prevents its degradation via the autophagosome/lysosome pathway. This process affects VLDL and LDL production and influences atherogenesis. Here, we investigated the molecular machinery by which PCSK9 modulates autophagy and affects atherogenesis. We backcrossed Pcsk9−/− mice with atherosclerosis-prone Ldlr−/−Apobec1−/− (LDb) mice to generate Ldlr−/−Apobec1−/−Pcsk9−/− (LTp) mice. Deletion of PCSK9 resulted in decreased hepatic apoB secretion, increased autophagic flux, and decreased plasma levels of IDL and LDL particles. The LDLs from LTp mice (LTp-LDLs) were less atherogenic and contained less cholesteryl ester and phospholipids than LDb-LDLs. Moreover LTp-LDLs induced lower endothelial expression of the genes encoding TLR2, Lox-1, ICAM-1, CCL2, CCL7, IL-6, IL-1β, Beclin-1, p62, and TRAF6. Collectively, these effects were associated with substantially less atherosclerosis development (>4-fold) in LTp mice. The absence of PCSK9 in LDb mice results in decreased lipid and apoB levels, fewer atherogenic LDLs, and marked reduction of atherosclerosis. The effect on atherogenesis may be mediated in part by the effects of modified LDLs on endothelial cell receptors and proinflammatory and autophagy molecules. These findings suggest that there may be clinical benefits of PCSK9 inhibition due to mechanisms unrelated to increased LDL receptor activity. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the LDL receptor (LDLR) and thereby promotes its intracellular degradation. This results in reduced hepatic LDL uptake and increased plasma LDL concentrations (1.Bergeron N. Phan B.A. Ding Y. Fong A. Krauss R.M. Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk.Circulation. 2015; 132: 1648-1666Crossref PubMed Scopus (127) Google Scholar). In 2003, Abifadel et al. (2.Abifadel M. Varret M. Rabes J.P. Allard D. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref PubMed Scopus (2168) Google Scholar) described gain-of-function mutations in the PCSK9 genes, which cause severe hypercholesterolemia. Studies in families from Utah (3.Timms K.M. Wagner S. Samuels M.E. Forbey K. Goldfine H. Jammulapati S. Skolnick M.H. Hopkins P.N. Hunt S.C. Shattuck D.M. A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree.Hum. Genet. 2004; 114: 349-353Crossref PubMed Scopus (269) Google Scholar), Norway (4.Leren T.P. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia.Clin. Genet. 2004; 65: 419-422Crossref PubMed Scopus (205) Google Scholar), and Britain (5.Sun X.M. Eden E.R. Tosi I. Neuwirth C.K. Wile D. Naoumova R.P. Soutar A.K. Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia.Hum. Mol. Genet. PubMed Scopus Google Scholar) these mutations in PCSK9 in a reduction in LDL A. C.K. LDL in of from mutations in Genet. PubMed Scopus Google Scholar) and associated with from the development of disease in and PubMed Scopus Google Scholar). the for the development of that lower LDL and as for therapeutic the PCSK9 R.P. N. H. et and and clinical in with cardiovascular PubMed Scopus Google Scholar). et al. M. A. D. S. C. A. of convertase subtilisin/kexin type 9 atherosclerosis in PubMed Scopus Google Scholar) that PCSK9 to the development of atherosclerosis in mice in et al. M. S. et inhibition to hepatic and atherosclerosis in the absence of PubMed Scopus Google Scholar) that and to the PCSK9 effect on atherosclerosis in mice. these suggest that PCSK9 to atherosclerosis development via the of by PCSK9 and the of PCSK9 to atherogenesis and that PCSK9 apoB and secretion autophagic process and that effect of the H. A. N. M. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular of the PubMed Scopus Google Scholar). 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A. et therapeutic of PubMed Scopus Google Scholar), gene that PCSK9 gene expression in the cardiovascular disease than be by of PCSK9 The and for The from the of and for of for and on the The the and on from from of Hopkins of and from with cholesteryl ester endothelial cell Ldlr−/−Apobec1−/− LDL receptor Ldlr−/−Apobec1−/−Pcsk9−/− endothelial cell PCSK9 convertase subtilisin/kexin type 9

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