title: Aggravated restenosis and atherogenesis in ApoCIII transgenic mice but lack of protection in ApoCIII knockouts: the effect of authentic triglyceride-rich lipoproteins with and without ApoCIII.
abstract: OBJECTIVE
  Previously, our group and others have demonstrated a causative relationship between severe hypertriglyceridaemia and atherogenesis in mice. Furthermore, clinical investigations have shown high levels of plasma Apolipoprotein C-III (ApoCIII) associated with hypertriglyceridaemia and even cardiovascular disease. However, it remains unclear whether ApoCIII affects restenosis in vivo, and whether such an effect is mediated by ApoCIII alone, or in combination with hypertriglyceridaemia. We sought to investigate ApoCIII in restenosis and clarify how smooth muscle cells (SMCs) respond to authentic triglyceride-rich lipoproteins (TRLs) with or without ApoCIII (TRLs ± ApoCIII).
  
  
  RESULTS
  ApoCIII transgenic (ApoCIIItg) and knockout (ApoCIII-/-) mice underwent endothelial denudation to model restenosis. Here, ApoCIIItg mice displayed severe hypertriglyceridaemia and increased neointimal formation compared with wild-type (WT) or ApoCIII-/- mice. Furthermore, increased proliferating cell nuclear antigen (PCNA)-positive cells, Mac-3, and vascular cell adhesion protein-1 (VCAM-1) expression, and 4-hydroxynonenal (4HNE) production were found in lesion sites. ApoCIIItg and ApoCIII-/- mice were then crossed to low-density lipoprotein receptor-deficient (Ldlr-/-) mice and fed an atherogenic diet. ApoCIIItg/Ldlr-/- mice had significantly increased atherosclerotic lesions. However, there was no statistical difference in restenosis between ApoCIII-/- and WT mice, and in atherosclerosis between ApoCIII/Ldlr double knockout and Ldlr-/- mice. SMCs were then incubated in vitro with authentic TRLs ± ApoCIII isolated from extreme hypertriglyceridaemia glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1-deficient (GPIHBP1-/-) mice crossed with ApoCIIItg or ApoCIII-/- mice. It was shown that TRLs + ApoCIII promoted SMC proliferation, VCAM-1 expression, and reactive oxygen species (ROS) production, and activated the Akt pathway. Scavenging ROS significantly reduced SMC activation caused by TRLs + ApoCIII.
  
  
  CONCLUSIONS
  Severe hypertriglyceridaemia resulting from ApoCIII overexpression promotes restenosis and atherosclerosis. Furthermore, we demonstrated that TRLs + ApoCIII promotes SMC proliferation.
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Han
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Qi
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Maomao
authors.initials: M
authors.lastname: Yu
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Mengyu
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medical University, No. 361, Zhongshan East Rd, Shijiazhuang 050017, China.
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Shu
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Brian
authors.initials: B
authors.lastname: Rodrigues
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medical University, No. 361, Zhongshan East Rd, Shijiazhuang 050017, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Han
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing 100191, China vangeorgeliu@gmail.com.
authors.forename: George
authors.initials: G
authors.lastname: Liu
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D053305:Apolipoprotein C-III / Q000235:genetics* / Q000378:metabolism*; D050197:Atherosclerosis / Q000378:metabolism*; D008074:Lipoproteins / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D053305:Apolipoprotein C-III; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D014280:Triglycerides; D019010:Vascular Cell Adhesion Molecule-1; C030087:lipoprotein triglyceride; C036763:monocyte-macrophage differentiation antigen
keywords: Apolipoprotein C-III; Atherosclerosis; Restenosis; Smooth muscle cell