title: Cross-talk between LOX-1 and PCSK9 in vascular tissues.
abstract: OBJECTIVE
  Lectin-like ox-LDL receptor-1 (LOX-1) plays an important role in inflammatory diseases, such as atherosclerosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates LDL receptor degradation and influences serum LDL levels. The present study was designed to investigate the possible interaction between PCSK9 and LOX-1.
  
  
  RESULTS
  In the first set of experiments, human vascular endothelial cells and smooth muscle cells were studied at baseline and after lipopolysaccharide (LPS) treatment (to create an inflammatory state). Both PCSK9 and LOX-1 were strongly induced by LPS treatment. To define the role of PCSK9 in LOX-1 expression, cells were transfected with siRNA against PCSK9, which resulted in reduced LOX-1 expression and function. On the other hand, cells exposed to recombinant hPCSK9 revealed enhanced LOX-1 expression (P < 0.05). To determine whether LOX-1 also regulates PCSK9, cultured cells in which LOX-1 was knocked down by siRNA expressed less PCSK9, whereas those transfected with hLOX-1 cDNA showed increased PCSK9 expression. The second set of experiments was carried out in wild-type (WT) and gene knockout (KO; LOX-1 and PCSK9) mice; LOX-1 KO mice showed much less PCSK9 (P < 0.05 vs. WT mice). PCSK9-KO mice showed much less LOX-1 (P < 0.05 vs. WT mice). Furthermore, we observed that mitochondrial reactive oxygen species (mtROS) plays an initiating role in the LOX-1/PCSK9 interaction, since mtROS induction enhanced and its inhibition reduced the expression of both PCSK9 and LOX-1. We also found that both LOX-1 and PCSK9 regulate adhesion molecules vascular cell adhesion molecule-1 expression. Finally, oxidized low-density lipoprotein and tumour necrosis factor-α, pro-inflammatory stimuli besides LPS, regulated PCSK9 expression that is mediated by the NF-κB signalling pathway.
  
  
  CONCLUSIONS
  These observations suggest that LOX-1 and PCSK9 positively influence each other's expression, especially during an inflammatory reaction. mtROS appear to be important initiators of PCSK9/LOX-1 expression.
authors.affiliation: Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China.
authors.forename: Zufeng
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China sliu2@uams.edu mehtajl@uams.edu.
authors.forename: Shijie
authors.initials: S
authors.lastname: Liu
authors.affiliation: Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Xianwei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Deng
authors.affiliation: Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Jiwani
authors.initials: J
authors.lastname: Shahanawaz
authors.affiliation: Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Shmookler Reis
authors.affiliation: Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Kattayi I
authors.initials: KI
authors.lastname: Varughese
authors.affiliation: Department of Physiology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto 390-8621, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sawamura
authors.affiliation: Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA sliu2@uams.edu mehtajl@uams.edu.
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C495138:Olr1 protein, mouse; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; D019010:Vascular Cell Adhesion Molecule-1; C099252:oxidized low density lipoprotein; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: LOX-1; Mitochondrial ROS; PCSK9; VCAM-1