title: Hepatic overexpression of the prodomain of furin lessens progression of atherosclerosis and reduces vascular remodeling in response to injury.
abstract: OBJECTIVE
  Atherosclerosis is a complex disease, involving elevated LDL-c, lipid accumulation in the blood vessel wall, foam cell formation and vascular dysfunction. Lowering plasma LDL-c is the cornerstone of current management of cardiovascular disease. However, new approaches which reduce plasma LDL-c and lessen the pathological vascular remodeling occurring in the disease should also have therapeutic value. Previously, we found that overexpression of profurin, the 83-amino acid prodomain of the proprotein convertase furin, lowered plasma HDL levels in wild-type mice. The question that remained was whether it had effects on apolipoprotein B (ApoB)-containing lipoproteins.
  
  
  METHODS
  Adenovirus mediated overexpression of hepatic profurin in Ldlr(-/-)mice and wild-type mice were used to evaluate effects of profurin on ApoB-containing lipoproteins, atherosclerosis and vascular remodeling.
  
  
  RESULTS
  Hepatic profurin overexpression resulted in a significant reduction in atherosclerotic lesion development in Ldlr(-/-)mice and a robust reduction in plasma LDL-c. Metabolic studies revealed lower secretion of ApoB and triglycerides in VLDL particles. Mechanistic studies showed that in the presence of profurin, hepatic ApoB, mainly ApoB100, was degraded by proteasomes. There was no effect on ApoB mRNA expression. Importantly, short-term hepatic profurin overexpression did not result in hepatic lipid accumulation. Blood vessel wall thickening caused by either wire-induced femoral artery injury or common carotid artery ligation was reduced. Profurin expression inhibited proliferation and migration in vascular smooth muscle cells in vitro.
  
  
  CONCLUSIONS
  These results indicate that a profurin-based therapy has the potential to treat atherosclerosis by improving metabolic lipid profiles and reducing both atherosclerotic lesion development and pathological vascular remodeling.
authors.affiliation: Department of Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Lei
authors.affiliation: Department of Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA.
authors.forename: Debapriya
authors.initials: D
authors.lastname: Basu
authors.affiliation: Department of Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Maoxiang
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: R Dan
authors.initials: RD
authors.lastname: Rudic
authors.affiliation: Department of Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA.
authors.forename: Xian-Cheng
authors.initials: XC
authors.lastname: Jiang
authors.affiliation: Department of Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA. Electronic address: weijun.jin@downstate.edu.
authors.forename: Weijun
authors.initials: W
authors.lastname: Jin
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D020212:Carotid Artery Injuries / Q000473:pathology; D017536:Carotid Artery, Common / Q000473:pathology; D008078:Cholesterol, LDL / Q000097:blood; D066273:Diet, Western / Q000009:adverse effects; D004730:Endothelium, Vascular / Q000293:injuries / Q000473:pathology; D005263:Femoral Artery / Q000293:injuries / Q000473:pathology; D045683:Furin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D018056:Hemorheology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008026:Ligation; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011973:Receptors, LDL / Q000172:deficiency; D011993:Recombinant Fusion Proteins / Q000378:metabolism
chemical_list: D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D011498:Protein Precursors; D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; C468731:FURIN protein, human; D045683:Furin; D046988:Proteasome Endopeptidase Complex
keywords: ApoB; Atherosclerosis; Furin; HDL; Prodomain; Typical proprotein convertase; VLDL; Vascular remodeling