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- TITLE: Scavenger Receptors and Their Potential as Therapeutic Targets in the Treatment of Cardiovascular Disease
- AUTHORS: Sam L. Stephen,Katie Freestone,Sarah Dunn,Michael W. Twigg,Shervanthi Homer-Vanniasinkam,John H. Walker,Stephen B. Wheatcroft,Sreenivasan Ponnambalam
JOURNAL NAME: International Journal of Hypertension
Sep 16, 2014
- ABSTRACT: Scavenger receptors act as membrane-bound and soluble proteins that bind to macromolecular complexes and pathogens. This diverse supergroup of proteins mediates binding to modified lipoprotein particles which regulate the initiation and progression of atherosclerotic plaques. In vascular tissues, scavenger receptors are implicated in regulating intracellular signaling, lipid accumulation, foam cell development, and cellular apoptosis or necrosis linked to the pathophysiology of atherosclerosis. One approach is using gene therapy to modulate scavenger receptor function in atherosclerosis. Ectopic expression of membrane-bound scavenger receptors using viral vectors can modify lipid profiles and reduce the incidence of atherosclerosis. Alternatively, expression of soluble scavenger receptors can also block plaque initiation and progression. Inhibition of scavenger receptor expression using a combined gene therapy and RNA interference strategy also holds promise for long-term therapy. Here we review our current understanding of the gene delivery by viral vectors to cells and tissues in gene therapy strategies and its application to the modulation of scavenger receptor function in atherosclerosis. 1. Introduction Scavenger receptors comprise a structurally diverse group of proteins . Originally identified by Brown and Goldstein, they were defined by their ability to bind modified forms of low density lipoprotein (LDL) including acetylated LDL (AcLDL) and oxidized LDL (OxLDL) and were thus implicated as key regulators in initiation and progression of atherosclerosis . This family of proteins has expanded to include eight different classes of membrane and soluble proteins (Class A, B, C, D, E, F, G, and H) encoded by distinct and unrelated genes . Scavenger receptor classes are grouped by the presence of shared structural domains; however there is great structural diversity between the different classes. Despite this lack of sequence similarity or identity, all scavenger receptors retain the capacity to bind modified lipid particles in addition to a diverse range of polyanionic ligands of host-derived or exogenous origins, for example, pathogens [4, 5]. 2. Genetics of Scavenger Receptors Class A scavenger receptors comprise at least four related genes: scavenger receptor A (SR-A), macrophage receptor with collagenous structure (MARCO), scavenger receptor with C-type lectin (SRCL), and scavenger receptor A-5 (SCARA5) [6–10]. The human and murine SR-A genes are located on chromosome 8 and can be transcribed to produce three (SR-AI/II/III) or two SR-A