Adeno-associated Virus-mediated Gene Transfer of a Secreted Decoy Human Macrophage Scavenger Receptor Reduces Atherosclerotic Lesion Formation in LDL Receptor Knockout Mice

doi:doi:10.1016/j.ymthe.2003.09.012

Molecular Therapy (2003) 8, 903–910; doi: 10.1016/j.ymthe.2003.09.012

Adeno-associated Virus-mediated Gene Transfer of a Secreted Decoy Human Macrophage Scavenger Receptor Reduces Atherosclerotic Lesion Formation in LDL Receptor Knockout Mice

Johanna Jalkanen¹, Pia Leppänen¹, Katri Pajusola², Outi Närvänen¹, Anssi Mähönen¹, Elisa Vähäkangas¹, David R. Greaves³, Hansruedi Büeler⁴ and Seppo Ylä-Herttuala^1,5,6

¹A. I. Virtanen Institute, FIN-70211 Kuopio, Finland
²Biomedicum, University of Helsinki, FIN-00014 Helsinki, Finland
³Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom
⁴Institute of Molecular Biology, University of Zurich, CH-8050 Zurich, Switzerland
⁵Department of Medicine, University of Kuopio, Finland
⁶Gene Therapy Unit, Kuopio University Hospital, FIN-70211 Kuopio, Finland

Correspondence: Seppo Ylä-Herttuala, A. I. Virtanen Institute, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland. Fax: +358-17-16 3751. E-mail: Seppo.YlaHerttuala@uku.fi

Received 20 August 2003; Accepted 17 September 2003.

Top

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.