Expression of Class A Scavenger Receptor Is Enhanced by High Glucose in Vitro and under Diabetic Conditions in Vivo

Abstract

In the early stage of atherosclerosis, macrophages take up chemically modified low density lipoproteins (LDL) through the scavenger receptors, leading to foam cell formation in atherosclerotic lesions. To get insight into a role of the scavenger receptors in diabetes-enhanced atherosclerotic complications, the effects on class A scavenger receptor (SR-A) of high glucose exposure in vitro as well as the diabetic conditions in vivo were determined in the present study. The in vitro experiments demonstrated that high glucose exposure to human monocyte-derived macrophages led to an increased SR-A expression with a concomitant increase in the endocytic uptake of acetylated LDL and oxidized LDL. The endocytic process was significantly suppressed by an anti-SR-A neutralizing antibody. Stability analyses revealed a significant increased stability of SR-A at a mRNA level but not a protein level, indicating that high glucoseinduced up-regulation of SR-A is due largely to increased stability of SR-A mRNA. High glucose-enhanced SR-A expression was prevented by protein kinase C and NAD(P)H oxidase inhibitors as well as antioxidants. High glucose-enhanced production of intracellular peroxides was visualized in these cells, which was attenuated by an antioxidant. The in vivo experiments demonstrated that peritoneal macrophages from streptozotocin-induced diabetic mice increased SR-A expression when compared with those from nondiabetic mice. Endocytic degradation of acetylated LDL and oxidized LDL were also increased with these macrophages but not with the corresponding macrophages from diabetic SR-A knock-out mice. These in vitro and in vivo results probably suggest that reactive oxygen species generated from a protein kinase C-dependent NAD(P)H oxidase pathway plays a role in the high glucose-induced up-regulation of SR-A, leading to the increased endocytic degradation of modified LDL for foam cell formation. This could be one mechanism for an increased rate of atherosclerosis in patients with diabetes.

Dietary glycotoxins affect scavenger receptor expression and the hormonal profile of female rats

“…In parallel, the expression of SR-A, which also showed a tendency towards decreased levels in the high-AGE diet-fed group, seems to contribute to the decreased clearance of AGEs, thus promoting AGE-related complications. Although SR-A-related published data are still controversial since high glucose or modified LDL are able to increase the expression of SR-A (Lam et al 2004, Fukuhara-Takaki et al 2005, while TNFa is able to decrease it in macrophages (Hsu et al 1996), even these in vitro or in vivo data cannot be compared to the peripheral monocytic SR-A expression and have a lot of differences to the AGEs receptors' regulation in the dietary glycotoxins model that we performed here. Another novel finding of this study is the possible link between the expression of scavenger receptors, such as RAGE, and the hormonal dysregulation of the female reproductive system, since the monocytic expression of RAGE was negatively correlated with testosterone levels and positively correlated with progesterone levels.…”

Hypoxia Modifies the Transcriptome of Primary Human Monocytes: Modulation of Novel Immune-Related Genes and Identification Of CC-Chemokine Ligand 20 as a New Hypoxia-Inducible Gene

“…Profound changes were observed in the expression of scavenger receptors. Of relevance is the up-regulation of MSR1 and SCARF1, because these molecules functions as endocytic receptors for acetylated LDL and may thus be implicated in lipidloaded foam cell formation contributing to atherosclerotic plaques development (50). Consistent with the view that hypoxia may exert a pathogenetic role in atherosclerosis and Alzheimer's disease (9,10,41) is also the down-regulation of CD163 and STAB1 scavenger receptors, which are endowed with atheroprotective activity (51,52), and of various genes involved in the regulation of fatty acid and/or cholesterol biosynthesis/transport and acting as antiatherogenic factors, e.g., LDLR, ApoE, and CYP27A1 (53,54).…”

MICA/B expression in macrophage foam cells infiltrating atherosclerotic plaques

“…Thus, SR-A expression is frequently observed in atherosclerotic lesions (Naito et al, 1992). Recent work has shown that exposure to high glucose in vitro enhances SR-A expression in human MDMs, accounting for the high incidence of atherosclerosis in diabetic patients (Fukuhara-Takaki et al, 2005). SR-A expression is also up-regulated by interferon-, providing a possible explanation for the high risk of atherosclerosis in patients with systemic lupus erythematosus (Li et al, 2011).…”