title: Adeno-associated virus-mediated gene transfer of a secreted decoy human macrophage scavenger receptor reduces atherosclerotic lesion formation in LDL receptor knockout mice.
abstract: Macrophage scavenger receptors (MSR) promote atherosclerotic lesion formation, and modulation of MSR activity has been shown to influence atherosclerosis. Soluble receptors are effective in inhibiting receptor-mediated functions in various diseases. We have generated a secreted macrophage scavenger receptor (sMSR) that consists of the bovine growth hormone signal sequence and the human MSR A I extracellular domains. sMSR reduces degradation of atherogenic modified low-density lipoproteins and monocyte/macrophage adhesion on endothelial cells in vitro. To test long-term effects of sMSR, atherosclerosis-susceptible LDLR knockout mice were transduced via the tail vein with an adeno-associated virus (AAV) expressing sMSR or control enhanced green fluorescent protein (EGFP), and a Western-type diet was started. Gene transfer caused a temporary elevation in alkaline phosphatase and aspartate amino transferase values without a change in C-reactive protein. sMSR protein was detected in the plasma of the transduced mice by a specific ELISA 6 months after the gene transfer. AAV-mediated sMSR gene transfer reduced atherosclerotic lesion area in the aorta by 21% (P < 0.05) compared to EGFP-transduced control mice. Even though eradication of established disease was not possible, atherosclerotic lesion formation could be modified using AAV-mediated gene transfer of the decoy sMSR.
authors.affiliation: A. I. Virtanen Institute, University of Kuopio, FIN-70211, Kuopio, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Jalkanen
authors.forename: Pia
authors.initials: P
authors.lastname: Leppänen
authors.forename: Katri
authors.initials: K
authors.lastname: Pajusola
authors.forename: Outi
authors.initials: O
authors.lastname: Närvänen
authors.forename: Anssi
authors.initials: A
authors.lastname: Mähönen
authors.forename: Elisa
authors.initials: E
authors.lastname: Vähäkangas
authors.forename: David R
authors.initials: DR
authors.lastname: Greaves
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Büeler
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001161:Arteriosclerosis / Q000473:pathology / Q000628:therapy*; D000229:Dependovirus; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008055:Lipids / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D051116:Receptors, Scavenger
chemical_list: D008055:Lipids; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D051116:Receptors, Scavenger