Adeno-associated virus-mediated gene transfer of a secreted decoy human macrophage scavenger receptor reduces atherosclerotic lesion formation in LDL receptor knockout mice

• Published in: Molecular therapy Vol. 8; no. 6; pp. 903 - 910
• Main Authors: Jalkanen, Johanna, Leppänen, Pia, Pajusola, Katri, Närvänen, Outi, Mähönen, Anssi, Vähäkangas, Elisa, Greaves, David R, Büeler, Hansruedi, Ylä-Herttuala, Seppo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2003; Elsevier Limited
• Subjects: adenoviruses; Animals; Aorta - pathology; Arteriosclerosis - pathology; Arteriosclerosis - therapy; Atherosclerosis; Cholesterol; Coronary vessels; Dependovirus; Disease; Gene therapy; gene transfer; Genetic Therapy; Genetic Vectors; Growth hormones; Humans; LDL receptor knockout mice; Lipids - blood; Lipoproteins; Liver; Low density lipoprotein receptors; macrophages; Mice; Mice, Knockout; Phosphatase; Plasma; Proteins; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Receptors, LDL - deficiency; Receptors, LDL - genetics; Receptors, Scavenger; scavenger receptor; Smooth muscle; Veins & arteries; Viruses; Finland; scavenger receptor; macrophages; adenoviruses; LDL receptor knockout mice; gene transfer
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2003.09.012

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.