title: Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice.
abstract: BACKGROUND
  The proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes independently of its enzymatic activity the degradation of the low-density lipoprotein (LDL) receptor. PCSK9 gain of function in humans leads to autosomal dominant hypercholesterolemia, whereas the absence of functional PCSK9 results in ≈7-fold lower levels of LDL cholesterol. This suggests that lowering PCSK9 may protect against atherosclerosis.
  
  
  RESULTS
  We investigated the role of PCSK9 in atherosclerosis in C57BL/6 wild-type (WT), apolipoprotein E-deficient, and LDL receptor-deficient mouse models. Circulating cholesterol levels, fast protein liquid chromatography profiles, aortic cholesteryl esters (CE), and plaque sizes were determined. Intima-media thicknesses were measured by ultrasound biomicroscopy. First, mice expressing null (knockout [KO]), normal (WT), or high (transgenic [Tg]) levels of PCSK9 were fed a 12-month Western diet. KO mice accumulated 4-fold less aortic CE than WT mice, whereas Tg mice exhibited high CE and severe aortic lesions. Next we generated apolipoprotein E-deficient mice, known to spontaneously develop lesions, that expressed null (KO/e), normal (WT/e), or high (Tg/e) levels of PCSK9. After a 6-month regular diet, KO/e mice showed a 39% reduction compared with WT/e mice in aortic CE accumulation, whereas Tg/e mice showed a 137% increase. Finally, LDL receptor-deficient mice expressing no (KO/L), normal (WT/L), or high (Tg/L) levels of PCSK9 were fed a Western diet for 3 months. KO/L and Tg/L mice exhibited levels of plasma cholesterol and CE accumulation similar to those of WT/L mice, suggesting that PCSK9 modulates atherosclerosis mainly via the LDL receptor.
  
  
  CONCLUSIONS
  Altogether, our results show a direct relationship between PCSK9 and atherosclerosis. PCSK9 overexpression is proatherogenic, whereas its absence is protective.
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, QC, H2W 1R7, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Denis
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Marcinkiewicz
authors.forename: Ahmed
authors.initials: A
authors.lastname: Zaid
authors.forename: Dany
authors.initials: D
authors.lastname: Gauthier
authors.forename: Steve
authors.initials: S
authors.lastname: Poirier
authors.forename: Claude
authors.initials: C
authors.lastname: Lazure
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.forename: Annik
authors.initials: A
authors.lastname: Prat
mesh_terms: D000367:Age Factors; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000209:etiology* / Q000517:prevention & control; D008078:Cholesterol, LDL / Q000097:blood; D004032:Diet; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000502:physiology; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012737:Sex Factors
chemical_list: D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D011973:Receptors, LDL; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases