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

J Lipid Res. 2018 Feb;59(2):207-223. doi: 10.1194/jlr.M078360. Epub 2017 Nov 27.


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.

Keywords: autophagy; low density lipoprotein; proprotein convertase subtilisin/kexin type 9.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apolipoproteins B / metabolism*
  • Atherosclerosis / metabolism*
  • Endothelium, Vascular / metabolism*
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proprotein Convertase 9 / deficiency
  • Proprotein Convertase 9 / metabolism*


  • Apolipoproteins B
  • Pcsk9 protein, mouse
  • Proprotein Convertase 9