title: Inducible ApoE gene repair in hypomorphic ApoE mice deficient in the low-density lipoprotein receptor promotes atheroma stabilization with a human-like lipoprotein profile.
abstract: OBJECTIVE
  To study atherosclerosis regression in mice after plasma lipid reduction to moderately elevated apolipoprotein B (apoB)-lipoprotein levels.
  
  
  RESULTS
  Chow-fed hypomorphic Apoe mice deficient in low-density lipoprotein receptor expression (Apoe(h/h)Ldlr(-/-)Mx1-cre mice) develop hyperlipidemia and atherosclerosis. These mice were studied before and after inducible cre-mediated Apoe gene repair. By 1 week, induced mice displayed a 2-fold reduction in plasma cholesterol and triglyceride levels and a decrease in the non-high-density lipoprotein:high-density lipoprotein-cholesterol ratio from 87%:13% to 60%:40%. This halted atherosclerotic lesion growth and promoted macrophage loss and accumulation of thick collagen fibers for up to 8 weeks. Concomitantly, blood Ly-6C(high) monocytes were decreased by 2-fold but lesional macrophage apoptosis was unchanged. The expression of several genes involved in extracellular matrix remodeling and cell migration was changed in lesional macrophages 1 week after Apoe gene repair. However, mRNA levels of numerous genes involved in cholesterol efflux and inflammation were not significantly changed at this time point.
  
  
  CONCLUSIONS
  Restoring apoE expression in Apoe(h/h)Ldlr(-/-)Mx1-cre mice resulted in lesion stabilization in the context of a human-like ratio of non-high-density lipoprotein:high-density lipoprotein-cholesterol. Our data suggest that macrophage loss derived in part from reduced blood Ly-6C(high) monocytes levels and genetic reprogramming of lesional macrophages.
authors.affiliation: Division of Vascular and Endovascular Surgery, Department of Surgery, VA Medical Center, University of California San Francisco, CA 94121, USA.
authors.forename: Delphine
authors.initials: D
authors.lastname: Eberlé
authors.forename: Fu Sang
authors.initials: FS
authors.lastname: Luk
authors.forename: Roy Y
authors.initials: RY
authors.lastname: Kim
authors.forename: Victor R
authors.initials: VR
authors.lastname: Olivas
authors.forename: Nikit
authors.initials: N
authors.lastname: Kumar
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Posada
authors.forename: Kang
authors.initials: K
authors.lastname: Li
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gaudreault
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Rapp
authors.forename: Robert L
authors.initials: RL
authors.lastname: Raffai
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000097:blood / Q000235:genetics; D001057:Apolipoproteins E / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D017209:Apoptosis / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D008264:Macrophages / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics*; D014280:Triglycerides / Q000097:blood
chemical_list: C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol
keywords: apolipoprotein E; atherosclerosis; macrophage; monocyte