Class A1 scavenger receptors in cardiovascular diseases

Class A1 scavenger receptors (SR‐A1) are membrane glycoproteins that can form homotrimers. This receptor was originally defined by its ability to mediate the accumulation of lipids in macrophages. Subsequent studies reveal that SR‐A1 plays critical roles in innate immunity, cell apoptosis and proliferation. This review highlights recent advances in understanding the structure, receptor pathway and regulation of SR‐A1. Although its role in atherosclerosis is disputable, recent discoveries suggest that SR‐A1 function in anti‐inflammatory responses by promoting an M2 macrophage phenotype in cardiovascular diseases. Therefore, SR‐A1 may be a potential target for therapeutic intervention of cardiovascular diseases.

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This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

Abbreviations

acLDL

acetylated low‐density lipoprotein

ER

endoplasmic reticulum

I/R

ischaemia/reperfusion

LTA

lipoteichoic acid

MI

myocardial infarction

mLDL

modified low‐density lipoprotein

oxLDL

oxidized low‐density lipoprotein

PRR

pattern recognition receptor

RAGE

receptor for advanced glycated end‐products

SR‐A1

class A1 scavenger receptor

TLR4

Toll‐like receptor 4

TRAF6

TNF receptor‐associated factor 6

Tables of Links

TARGETS
Catalytic receptorsa
Mer receptor tyrosine kinase
TLR4
Enzymesb
Caspase 3
ERK
JNK
Mitogen‐activated protein kinase kinase 7 (MKK7)
p38
PI3K
PKC
PLC‐γ1

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LIGANDS
Amyloid β
IFN‐γ
IL‐1
IL‐10
LPS
Lysophosphatidylcholine
Macrophage colony‐stimulating factor (M‐CSF)
MMP‐9
Phorbol ester (PMA)
Phosphatidylserine
TGF‐β1
TNF‐α

Open in a separate windowThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 (^a,bAlexander et al., 2013a, 2013b).Scavenger receptors are cell surface receptors that are structurally diverse but they typically recognize many different ligands to participate in diverse biological functions. The functional mechanisms of scavenger receptors include endocytosis, phagocytosis, adhesion and signalling, which ultimately leads to the removal of non‐self‐ or altered self‐targets. There are 10 classes of scavenger receptors according to a unified nomenclature system for scavenger receptors (Prabhudas et al., 2014). Class A scavenger receptors have several structural features in common, including a cytoplasmic tail, a transmembrane domain, a spacer region, a helical coiled coil domain, a collagenous domain and a C‐terminal cysteine‐rich domain (Figure 1). Class A1 scavenger receptor (SR‐A1), also known as SCARA1, CD204 or macrophage scavenger receptor 1, is the prototypical SR‐A molecule and was the first scavenger receptor to be identified (Goldstein et al., 1979; Kodama et al., 1990; Rohrer et al., 1990)Open in a separate windowFigure 1Members of class A scavenger receptor family. The members of class A scavenger receptor family have a similar structure that is composed of a cytoplasmic tail, a transmembrane domain, a spacer region, a helical coiled coil domain, a collagenous domain and a C‐terminal cysteine‐rich domain.SR‐A1 was initially identified by its ability to mediate the formation of foam cells, a characteristic component of atherosclerotic lesions (Goldstein et al., 1979; Kodama et al., 1990; Krieger and Herz, 1994; Bowdish and Gordon, 2009). However, observations from various SR‐A1 gene knockout mouse models have yielded discrepant results concerning its role in the occurrence and development of atherosclerotic lesions (Suzuki et al., 1997; Kuchibhotla et al., 2008; Manning‐Tobin et al., 2009). A role beyond the handling of cholesterol is emerging for SR‐A1 in the pathogenesis of cardiovascular diseases. It not only functions as a phagocytic receptor and an innate immune recognition receptor but also plays an important role in cell apoptosis and cell proliferation. An overview of the recent progress of SR‐A1 structure, signal transduction and its roles in cardiovascular diseases will be provided in this review.