title: Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice.
abstract: Lipoprotein glomerulopathy (LPG) is a renal disease often accompanied by dyslipidemia and increased serum apoE levels. apoESendai (Arg145Pro), a rare mutant based on the apoE3 sequence carrying an apoE2 charge, causes LPG in humans and transgenic mice, but its effects on the artery wall are unknown. Macrophage expression of apoESendai may also directly influence renal and arterial homeostasis. We investigated the effects of macrophage-expressed apoESendai in apoE(-/-) mice with or without LDL receptor (LDLR). Murine bone marrow transduced to express apoE2, apoE3, or apoESendai was transplanted into lethally irradiated mice. Macrophage apoESendai expression reduced aortic lesion size and inflammation by 32 and 28%, respectively, compared with apoE2 in apoE(-/-) recipients. No differences in lesion size or inflammation were found between apoESendai and apoE3 in apoE(-/-) recipients. Macrophage apoESendai expression also reduced aortic lesion size by 18% and inflammation by 29% compared with apoE2 in apoE(-/-)/LDLR(-/-) recipients. Glomerular lesions compatible with LPG with increased mesangial matrix, extracellular lipid accumulation, and focal mesangiolysis were only observed in apoE(-/-)/LDLR(-/-) mice expressing apoESendai. Thus, macrophage expression of apoESendai protects against atherosclerosis while causing lipoprotein glomerulopathy. This is the first demonstration of an apoprotein variant having opposing effects on vascular and renal homeostasis.
authors.affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR Section of Cardiovascular Disease Prevention, Division of Cardiovascular Medicine, Departments of Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Hagai
authors.initials: H
authors.lastname: Tavori
authors.affiliation: Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC.
authors.forename: Daping
authors.initials: D
authors.lastname: Fan
authors.affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Giunzioni
authors.affiliation: Section of Cardiovascular Disease Prevention, Division of Cardiovascular Medicine, Departments of Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Section of Cardiovascular Disease Prevention, Division of Cardiovascular Medicine, Departments of Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
authors.affiliation: Pathology, Immunology, and Microbiology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR Section of Cardiovascular Disease Prevention, Division of Cardiovascular Medicine, Departments of Medicine, Vanderbilt University Medical Center, Nashville, TN Pathology, Immunology, and Microbiology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000096:biosynthesis* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D011973:Receptors, LDL
keywords: apolipoprotein ESendai; lipoprotein glomerulopathy; macrophage