Expression of CD36 in macrophages and atherosclerosis: the role of lipid regulation of PPARgamma signaling

Several macrophage scavenger receptors have been identified that bind and internalize modified low-density lipoprotein particles. Although the pathophysiologic roles played by these receptors in human disease are still unproven, data from murine models of atherosclerosis have demonstrated a significant role in atherosclerotic foam cell development and vascular lesion development for two receptors: the type A scavenger receptor (SR-A) and the type B scavenger receptor, CD36. This review addresses the regulation and potential role of CD36 in macrophage foam cell formation and atherosclerosis, with particular emphasis on the mechanisms by which CD36 expression is altered in response to lipid modulation of peroxisome proliferator-activated receptor gamma signaling.     

B类清道夫受体CD36在糖尿病动脉粥样硬化发病机制中的作用研究进展

糖尿病是动脉粥样硬化（atherosclerosis,AS）最重要的独立危险因素,但糖尿病导致AS的确切机制至今仍不完全清楚。研究表明,CD36是AS发生、发展过程中重要的调控分子,对CD36在糖尿病性动脉粥样硬化发生、发展过程中的作用进行深入的研究,有利于进一步揭示糖尿病动脉粥样硬化的机制,从而指导临床防治工作。     

CD36的结构、功能调节及其在动脉粥样硬化中的作用

CD36是一种多功能跨膜糖蛋白,介导细胞对氧化型低密度脂蛋白(ox-LDL)的摄取,诱导单核细胞转化为泡沫细胞,并通过炎症反应、氧化应激、血小板活化、巨噬细胞捕获促进动脉粥样硬化形成。抑制CD36的表达或干扰其相关信号通路可以显著缓解动脉粥样硬化的严重程度。另外,舌、鼻腔、小肠和大脑的CD36高表达可促进机体对脂质摄入和吸收,增加代谢性疾病的疾病危险因素。血清可溶性CD36是循环微粒的组分,且可能是心血管疾病的预测因子。     

阿托伐他汀对THP-1巨噬细胞CD36表达的影响

目的研究阿托伐他汀(atorvastatin)对THP-1巨噬细胞B类清道夫受体CD36表达的影响。方法用5!mol/L阿托伐他汀与THP-1巨噬细胞孵育不同时间;用不同浓度的阿托伐他汀与THP-1巨噬细胞共同孵育24h,采用RT-PCR与Westernblotting分别检测THP-1巨噬细胞CD36mRNA与蛋白质的表达。结果阿托伐他汀使THP-1巨噬细胞CD36mRNA与蛋白质的表达下调(P<0.05),且时间与剂量呈依赖关系。结论阿托伐他汀能抑制THP-1巨噬细胞CD36的表达。     

2型糖尿病患者血浆可溶性CD36与动脉粥样硬化的关系

目的 分析T2DM患者血浆可溶性CD36（sCD36）水平与动脉粥样硬化（AS）的关系.方法 纳入T2DM患者88例,根据颈动脉彩色超声结果分为颈动脉粥样斑块（AS）组38例,无斑块对照（CG）组50例.测定并分析两组血浆sCD36及血清25-羟维生素D3[25-（OH）D3]水平与动脉斑块的关系.结果 与CG组相比,AS组sCD36[（2.21±0.91）vs（1.61±0.52）]、HbA1c、LDL-C升高,25-（OH） D3[13.33（4.19,15.85） vs 20.58（6.06,31.10）]降低（P＜0.05）.多元回归分析显示,sCD36、HbA1c、LDL-C是AS的危险因素.25-（OH）D3水平降低（R2=0.08,β=-0.28,P＜0.01）是sCD36升高的影响因素.结论 T2DM患者血浆sCD36可能是其发生AS的生化标志物.     

Unsaturated fatty acids and their oxidation products stimulate CD36 gene expression in human macrophages

Fatty acids (FA) have been implicated in the control of expression of several atherosclerosis-related genes. Similarly, the CD36 receptor has recently been shown to play an important role in atherosclerosis and other pathologies. The aim of the present study was to evaluate the direct effect of FA and their oxidation products (aldehydes), on the expression of CD36 in both THP-1 macrophages and human monocyte-derived macrophages (HMDM). The FA tested included the saturated FA (SFA) lauric, myristic, palmitic and stearic acid; the monounsaturated FA oleic acid; and the unsaturated FA (UFA) linoleic, arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Aldehydes used were malondialdehyde (MDA), hexanal, 2,4-decadienal (DDE) and 4-hydroxynonenal (HNE). CD36 expression was measured by RT-PCR, Western blot and immunofluorescence. Incubation of THP-1 macrophages for 24 h with non-cytotoxic concentrations of UFA significantly increased CD36 mRNA expression. By contrast, exposure of THP-1 macrophages to SFA did not affect the levels of CD36 mRNA. Among all UFAs tested, EPA and DHA were the strongest inducers of CD36 mRNA levels, followed by oleic and linoleic acid. Incubation of HMDM with either oleic or linoleic acid significantly increased steady-state CD36 mRNA in a dose-dependent manner. Consistent with the increase of CD36 mRNA expression, incubation of THP-1 macrophages with oleic and linoleic acid for 24 h markedly increased CD36 protein expression. Treatment of THP-1 macrophages with MDA or hexanal for 24 h significantly increased CD36 mRNA expression in a dose dependent manner. In contrast, DDE and HNE significantly decreased this parameter. The data provide evidence for a direct regulatory effect of UFA on CD36 gene expression and support a role for aldehydes in the regulation of CD36 expression by FA.     

CD36 mediates the phagocytosis of Plasmodium falciparum-infected erythrocytes by rodent macrophages

Phagocytic cells represent an important line of innate defense against malaria; however, little is known of the mechanism by which macrophages recognize Plasmodium falciparum-parasitized erythrocytes (PEs). Using macrophages from CD36 wild-type (WT), CD36-null, and CD36 transgenically-rescued rodents, we demonstrate a major role for CD36 in the phagocytosis of PEs. WT macrophages display enhanced phagocytic capacity for nonopsonized PEs, compared with that for CD36-null mouse and rat macrophages. Transgenic rescue of CD36-deficient rats restored macrophage phagocytic capacity for PEs. CD36 receptor blockade with monoclonal antibodies and proteolytic cleavage of CD36 ligands from the surface of PEs inhibited the uptake of PEs. Up-regulation of rodent CD36 by use of peroxisome proliferator-activated receptor (PPARgamma) agonists increased the phagocytosis of PEs. CD36-mediated uptake of PEs did not result in increased tumor necrosis factor-alpha secretion, of which high levels are associated with adverse outcomes in malaria. These studies support the use of these rodent models to examine PE-CD36 interactions.     

Complex connection between CD36 and atherosclerosis, lipid metabolism, and insulin resistance syndromes

Conclusions Emerging evidence sheds light on the link between CD36 and the development of atherosclerosis, dyslipidemia, and IRS. The mechanism of the link, however, is still unclear. This is due in part to the tissue-specific, multifunctional feature of CD36 (eg, a dual receptor for lipoproteins in macrophages and for fatty acids in adipocytes). In addition, the species-specific differences observed in phenotypes of CD36 deficiency further complicate the connection. Some of these differences may be explained by differences independent of CD36 (eg, differences in the activity of cholesteryl ester transfer protein between human and rodents). However, it also seems likely that there is some species-specific compensation mechanism for the loss of a certain function of CD36, possibly in a tissue-specific manner (eg, compensation of the function of CD36 as FAT by other membranous fatty acid binding proteins). Careful comparison between the phenotypes observed in human, mouse, and rat CD36 deficiency will shed light on this connection and give new insight on atherogenesis and lipid metabolism.     

Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL

Atherosclerotic coronary heart disease is a common complication of the insulin resistance syndrome that can occur with or without diabetes mellitus. Thiazolidinediones (TZDs), which are insulin-sensitizing antidiabetic agents, can modulate the development of atherosclerosis not only by changing the systemic metabolic conditions associated with insulin resistance but also by exerting direct effects on vascular wall cells that express peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear receptor for TZDs. Here we show that troglitazone, a TZD, significantly inhibited fatty streak lesion formation in apolipoprotein E-knockout mice fed a high-fat diet (en face aortic surface lesion areas were 6.9+/-2.5% vs 12.7+/-4.7%, P<0.05; cross-sectional lesion areas were 191 974+/-102 911 micrometer(2) vs 351 738+/-175 597 micrometer(2), P<0.05; n=10). Troglitazone attenuated hyperinsulinemic hyperglycemia and increased high density lipoprotein cholesterol levels. In the aorta, troglitazone markedly increased the mRNA levels of CD36, a scavenger receptor for oxidized low density lipoprotein, presumably by upregulating its expression, at least in part, in the macrophage foam cells. These results indicate that troglitazone potently inhibits fatty streak lesion formation by modulating both metabolic extracellular environments and arterial wall cell functions.     

Aspirin increases CD36, SR-BI, and ABCA1 expression in human THP-1 macrophages

OBJECTIVE: CD36 is a receptor, whose expression increases during the differentiation of monocytes to macrophages, playing a key role in the phagocytosis of apoptotic cells and in the formation of foam cells during atherosclerosis. Recently, it has been described that ligands of PPARgamma induce CD36 expression and inhibit cyclooxygenase expression in macrophages. Our aim was to study whether the reduction of endogenous prostaglandin production could modify CD36 expression in macrophages and to outline the potential mechanism. METHODS AND RESULTS: CD36 expression was measured by flow cytometry in THP-1 cells differentiated to macrophages that had been incubated with aspirin (ASA) alone or in combination with PGE(2), sulprostone (EP1/EP3 agonist), butaprost (EP2 agonist,) and PGE1 alcohol (EP2/EP4 agonist). Aspirin induced CD36 expression. Only PGE(2) and PGE1 alcohol completely abolished CD36 induction by aspirin, whereas butaprost strongly reduced it. BADGE (a PPARgamma antagonist) or diclofenac (a PPARgamma antagonist and a cyclooxygenase inhibitor) in aspirin-incubated cells did not reduce CD36 induction. On the other hand, aspirin also induced the expression of SR-BI and ABCA1, an HDL receptor and an HDL formation-related protein, respectively. CONCLUSIONS: Aspirin produces an increase of CD36 expression in THP-1 macrophages by a PGE(2)-dependent mechanism. The PGE(2) receptors implicated in CD36 modulation by ASA are the EP2/EP4 subtypes. Further, we provide evidence of SR-BI and ABCA1 induction by aspirin treatment.     

CD36与动脉粥样硬化

CD36是在多种组织细胞上表达的跨膜糖蛋白,属于B族清道夫受体.单核巨噬细胞上的CD36是吞噬摄取氧化型低密度脂蛋白的主要受体.除介导泡沫细胞形成外,CD36还有促进凝血和单核细胞聚集,促进炎症反应和氧化、凋亡等多种功能,其表达可被高度调控,是巨噬细胞泡沫化和动脉粥样硬化发生发展的重要因素.     

Variants of CD36 gene and their association with CD36 protein expression in platelets

Background

The relationship between CD36 expression level in platelets and polymorphism of the CD36 gene still needs to be explored. Here, we investigated polymorphisms of the CD36 gene and CD36 expression level in platelets in the Chinese Han population.

Materials and methods

A total of 477 samples were sequenced for exons 2 to 14 of the CD36 gene using a polymerase chain reaction sequence-based typing method. In 192 of these individuals the expression levels of CD36 antigen were analysed by flow cytometry. The genotype-phenotype relationship in platelets was analysed.

Results

A total of 22 variants of the CD36 gene were identified, of which five variants (111 A>T, 681 C>A, 1172–1183 del12b, 1236 delT and 1395 A>C) were novel variations, and nine were also found in single nucleotide polymorphism database (dbSNP) but had not been confirmed in individuals with CD36 deficiency. Two variants (329–332 delAC and 1228–1239 del12bp) in the coding region are the most frequent mutations in the Chinese population. Type II CD36 deficiency was identified in seven of 192 individuals, giving a frequency of 3.6%. Individuals with CD36 variations or wild-type genotypes both showed CD36 antigen negative, low-level and high-level expression patterns in platelets. The frequency of the nt-132 A>C polymorphism in the 5′-UTR is relatively high in the Chinese population (0.3516): the expression of CD36 was lower in individuals with nt-132 A>C than in those with the wild-type genotype.

Discussion

The distribution of CD36 gene variants in the Chinese population is different from that previously reported. The levels of expression of CD36 antigen in platelets are not determined directly by the genotypes of the CD36 coding region. This suggests that the molecular basis of type II CD36 deficiency may be derived from combined effects of coding region and potential cis-regulatory elements in the 5′-UTR of the CD36 gene.     

CD40 and its ligand in atherosclerosis

CD40-CD40 ligand (CD40L) interactions play a central role in the development and progression of atherosclerosis. In the late 1990s, we and others have shown that complete inhibition of the CD40L signaling pathway resulted in a decrease in atherosclerosis and in the induction of a stable atherosclerotic plaque phenotype. These stable plaques contained high amounts of collagen and vascular smooth muscle cells, whereas the amount of macrophages and T lymphocytes was low. Because clinical complications of atherosclerosis are mostly the result of plaque rupture, induction of plaque stability would significantly reduce the morbidity and mortality of atherosclerosis and thus validates inhibition of the CD40L system as a therapeutic target for atherosclerosis. However, long-term inhibition of this system probably compromises the immune system of the patient. Therefore, it is desirable to target either the downstream signaling modulators of the CD40-CD40L system that are associated with atherosclerosis, or target the CD40-CD40L system in a local, cell type-specific way. This is likely to induce plaque stabilization with limited systemic side effects, and a significant reduction of cardiovascular disease.     

CD40/CD40L系统与动脉粥样硬化

动脉粥样硬化是一种慢性炎症性疾病.动脉粥样硬化斑块破裂和血栓形成可导致急性心脑血管事件.炎性介质CD40/CD40L广泛存在于与动脉粥样硬化相关的细胞,参与斑块内炎症反应,释放促炎细胞因子,降解细胞外基质,提高促凝活性,促进动脉粥样硬化的进展和斑块易损性.干预CD40/CD40L信号系统可能成为减缓动脉粥样硬化进展和稳定动脉粥样硬化斑块的一种有效治疗策略.