AGEs inhibit scavenger receptor class B type I gene expression via Smad1 in HUVECs

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  • 1 Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa, Japan
  • | 2 Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  • | 3 Life Science Research Center, Kagawa University, Miki-cho, Kagawa, Japan

Correspondence should be addressed to K Murao: mkoji@med.kagawa-u.ac.jp
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Vascular complications are the main cause of morbidity and mortality in diabetic patients, and advanced glycation end products (AGEs) play a critical role in promoting diabetic vascular dysfunction. The human homolog of scavenger receptor class B type I (SR-BI), CD36, and LIMPII analog-1 (hSR-BI/CLA-1) facilitates the cellular uptake of cholesterol from HDL. In endothelial cells, HDL activates endothelial nitric oxide synthase (eNOS) via hSR-BI/CLA-1. In this study, we elucidated the effects of AGEs on hSR-BI/CLA-1 expression in human umbilical vein endothelial cells (HUVECs). HSR-BI/CLA-1 expression was examined by real-time PCR, western blot analysis, and reporter gene assay in HUVECs incubated with AGEs. eNOS activity was assessed by detecting the phosphorylation (Ser 1179) of eNOS. Our results showed that AGEs decreased the endogenous expression of hSR-BI/CLA-1. AGEs also inhibited the activity of the hSR-BI/CLA-1 promoter and its mRNA expression via receptor RAGE. We identified the binding site for Smad1 on the hSR-BI/CLA-1 promoter: Smad1 bound to its promoter. AGE treatment stimulated the transcriptional activity of Smad1, and mutation of the Smad1 binding site inhibited the effect of AGEs on the hSR-BI/CLA-1 promoter. HDL-treatment enhanced the phosphorylation of eNOS at Ser 1179, but pretreatment with AGEs inhibited the phosphorylation of eNOS Ser 1179. These results suggested that AGEs downregulate the expression of the endothelial hSR-BI/CLA-1 via the Smad1 pathway, which may be a therapeutic target for diabetic endothelial dysfunction.

Abstract

Vascular complications are the main cause of morbidity and mortality in diabetic patients, and advanced glycation end products (AGEs) play a critical role in promoting diabetic vascular dysfunction. The human homolog of scavenger receptor class B type I (SR-BI), CD36, and LIMPII analog-1 (hSR-BI/CLA-1) facilitates the cellular uptake of cholesterol from HDL. In endothelial cells, HDL activates endothelial nitric oxide synthase (eNOS) via hSR-BI/CLA-1. In this study, we elucidated the effects of AGEs on hSR-BI/CLA-1 expression in human umbilical vein endothelial cells (HUVECs). HSR-BI/CLA-1 expression was examined by real-time PCR, western blot analysis, and reporter gene assay in HUVECs incubated with AGEs. eNOS activity was assessed by detecting the phosphorylation (Ser 1179) of eNOS. Our results showed that AGEs decreased the endogenous expression of hSR-BI/CLA-1. AGEs also inhibited the activity of the hSR-BI/CLA-1 promoter and its mRNA expression via receptor RAGE. We identified the binding site for Smad1 on the hSR-BI/CLA-1 promoter: Smad1 bound to its promoter. AGE treatment stimulated the transcriptional activity of Smad1, and mutation of the Smad1 binding site inhibited the effect of AGEs on the hSR-BI/CLA-1 promoter. HDL-treatment enhanced the phosphorylation of eNOS at Ser 1179, but pretreatment with AGEs inhibited the phosphorylation of eNOS Ser 1179. These results suggested that AGEs downregulate the expression of the endothelial hSR-BI/CLA-1 via the Smad1 pathway, which may be a therapeutic target for diabetic endothelial dysfunction.

Introduction

Coronary atherosclerotic disease (CAD) is the number one cause of premature death in modern societies. Morbidity and mortality among people with diabetes mellitus are mostly caused by premature cardiovascular disease (CVD) (Rao Kondapally Seshasai et al. 2011). The advanced glycation end products (AGEs) receptor (RAGE) axis plays an important role in the pathogenesis of diabetic microangiopathy (Nin et al. 2011). AGEs result from the nonenzymatic reactions of reducing sugars with proteins, lipids, and nucleic acids, potentially altering their function by disrupting molecular conformation, promoting cross-linking, altering enzyme activity, reducing their clearance, and impairing receptor recognition. Elevated levels of circulating AGEs in the presence of hyperglycemia are believed to play a major role in the pathogenesis of macrovascular and microvascular diseases, observed in diabetes mellitus (Nin et al. 2011).

High-density lipoprotein (HDL) particles play a critical role in cholesterol metabolism, as they mediate a normal physiological process, known as reverse cholesterol transport (RCT) (Glomset 1968). In this process, HDL particles shuttle cholesterol from extra-hepatic tissues to the liver for further metabolism and excretion (Tall 1990). Mouse scavenger receptor class B type I (SR-BI) mediates the selective uptake of HDL cholesterol ester in transfected Chinese hamster ovary (CHO) cells. This finding provides an important link between a specific cell surface receptor and a pathway for the uptake of HDL (Acton et al. 1996). Our previous reports indicate that CD36 and LIMPII analog-1 (hSR-BI/CLA-1), like mouse SR-BI, function as a receptor for HDL (Murao et al. 1997, Imachi et al. 2003). However, the atheroprotective mechanism of HDL is complex and requires further investigation. Expression of hSR-BI/CLA-1 is detected not only in the liver but also in vascular endothelial cells (Yuhanna et al. 2001). Endothelial dysfunction plays a pivotal role in the initiation and progression of atherosclerosis. The vascular endothelium modulates the vessel tone by releasing both relaxation and contractile factors (Pedrinelli et al. 1994), regulates vascular permeability and the adherence of mononuclear cells to its surface (Bloom 1991), and produces factors involved in the regulation of hemostasis and tissue proliferation (Yuhanna et al. 2001). The release of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) plays an important role in the regulation of cardiovascular homeostasis. Previous reports indicate that hSR-BI/CLA-1 and eNOS are colocalized in vascular endothelial cells (Yuhanna et al. 2001, Yu et al. 2007). Thus, HDL activates eNOS via hSR-BI/CLA-1; the resulting increase in nitric-oxide production might be critical to the atheroprotective properties of HDL (Yuhanna et al. 2001, Stirban et al. 2006, Yu et al. 2007).

Several reports have indicated that AGEs promote the development of endothelial dysfunction in diabetic patients (Stirban et al. 2006, Soro-Paavonen et al. 2010). In vascular endothelial cells, AGEs were able to reduce NO production and eNOS expression under high glucose conditions (Soro-Paavonen et al. 2010). In the present study, we investigated the effect of AGEs on hSR-BI/CLA-1 expression in human umbilical vascular endothelial cells (HUVECs) to clarify the role of AGEs on HDL-mediated NOS activation.

Materials and methods

Cell culture

HUVECs were purchased from Dainippon Pharmaceutical Co, Ltd., (Osaka, Japan) and used between passages 1–6. HUVECS were maintained in Dulbecco’s modified Eagle’s medium (DMEM) (Sigma), supplemented with 10% heat-inactivated fetal bovine serum (Dainippon Pharmaceutical Co, Ltd.) in a humidified atmosphere with 5% CO2 at 37°C, as previously described (Yu et al. 2007). After 6-h starvation with DMEM, HUVECs were treated with AGEs-BSA (BVN; 222110) at varying dose for 24 h or at 100 μg/mL for varying time. For blockade of RAGE, HUVECs were treated with AGEs-BSA at 100 μg/mL together with anti-RAGE antibody (Santa Cruz; sc-365154) at 5 μg/mL for 24 h.

Western blot analysis

Protein samples (15 µg) were separated by 7.5% sodium dodecyl sulfate-PAGE (SDS-PAGE) under reducing conditions. The membranes were incubated with either anti-hSR-BI/CLA-1 antibody (1:3000 dilution), or anti-GAPDH antibody (1:1000 dilution; Biomol Research, Plymouth Meeting, PA) in phosphate buffered saline with 0.1% Tween 20 (PBS-T), as described previously (Murao et al. 2008a). Antibody binding was detected using ECL (Amersham Corp., Arlington Heights, IL).

Real-time polymerase chain reaction

Real-time Polymerase chain reactions (real-time PCRs) were performed in a final volume of 20 μL in a LightCycler® (Roche, Mannheim, Germany). The reaction mixture consisted of 2 μL LightCycler® FastStart DNA Master SYBR Green I (Roche), 2.4 μL of 25 mM MgCl2, 11.6 μL of sterile PCR-grade H2O, 2 μL of the cDNA template for each gene, and 1 μL of each primer (10 µM). The forward and reverse primers for human SR-BI/CLA-1 were 5′-TTGAACTTCTGGGCAAATG-3′ and 5′-TGGGGATGCCTTCAAACAC-3′, respectively. The PCR protocol was as follows: initial denaturation at 95°C for 60 s, and then 55 cycles of denaturation at 95°C for 5 s, annealing at 62°C for 5 s, and extension at 72°C for 15 s. Each set of reactions included water as a negative control, and five dilutions of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) DNA were used to calculate a standard curve, generated by the LightCycler® as described previously (Murao et al. 2008a).

Plasmid preparation

The reporter construct contained the sequence of the hSR-BI/CLA-1 gene from positions -1200 to +2, as described previously (Cao et al. 1997). The segment of interest was PCR amplified, and then cloned into a luciferase reporter vector (pCLA-LUC) as previously described (Murao et al. 2008a). Reporter containing 12 copies of the GCCG motif, the consensus sequence for Smad1, was constructed as described previously (Kusanagi et al. 2000).

Transfection of HUVECs and luciferase reporter gene assay

Purified reporter plasmids were transfected into HUVECs using lipofectamine (Life Technologies, Gaithersburg, MD) as described previously. All assays were corrected for β-galactosidase activity, and the total amount of protein in each reaction was identical, as previously described (Fukata et al. 2014). 20 μL Aliquots were used for the luciferase assay (ToyoInk, Tokyo, Japan).

Immunoblot of eNOS

After treatment of AGEs, HUVECs were treated with or without HDL (Bio-Rad, 5685-2004) at 10 μg/mL for 15 min and total protein was extracted from these cells. Protein samples were separated by 7.5% sodium dodecyl sulfate-PAGE (SDS-PAGE). A phospho-specific eNOS polyclonal antibody (1:500 dilution; Upstate Biotechnology, NY) was used to detect the phosphorylation of eNOS Ser1179. Similarly, phosphorylation-independent antibodies (Upstate Biotechnology) were used to detect total eNOS (diluted 1:500, Upstate Biotechnology, NY), as described previously (Fukata et al. 2014).

Chromatin immunoprecipitation (ChIP) assay

ChIP assay was performed using the ChIP-IT™ kit (Active Motif) according to the manufacturer’s instructions. Chromatin was immunoprecipitated with 2 μg of either rabbit Smad1 antibody (Cell Signaling Technology), or negative control IgG. PCR was carried out to amplify regions containing the putative Smad1 response sequence on hSR-BI/CLA-1 promoter as described previously (Cao et al. 1997), by using the following primers: Forward 5’-GCATAAAACCACTGGCCACCT-3’; Reverse 5’-GACGGCGACAGAGACGACACAG-3’. PCR was performed using TAKARA PCR thermal cycler MP in following amplification conditions: 94°C for 3 min, followed by 36 cycles of 94°C for 20 s, 58°C for 30 s, and 72°C for 30 s. Specific PCR products (117 bp) were detected by 2% agarose gel electrophoresis.

DNA analysis

To investigate the conserved transcription factor binding sites, the human SR-BI/CLA-1 genomic sequence of 208-bp upstream of transcription start sites (TSS; not including TSS) and 150-bp downstream of TSS (including TSS) was aligned to the corresponding mouse genomic sequence by BLASTZ (Pruitt et al. 2005) with its default setting. The particular genomic sequences were excised from RefSeq (Schwartz et al. 2003); NC_000012.10 for human and NC_000071.5 for mouse.

Statistical analysis

Data was expressed as mean ± s.e.m. Results were analyzed by one-way ANOVA and Student’s t test. P < 0.05 was considered statistically significant. All experiments were performed at least three times.

Results

AGEs decrease hSR-BI/CLA-1 expression in HUVECs

To analyze the effects of AGEs on hSR-BI/CLA-1 expression, we treated HUVECs with AGEs, and performed a western blot analysis to measure the level of endogenous hSR-BI/CLA-1 expression. AGEs decreased the amount of endogenous hSR-BI/CLA-1 protein in a dose-dependent manner (Fig. 1A). In addition, AGEs decreased the expression of hSR-BI/CLA-1 mRNAs in HUVECs. The maximum effect was observed 24 h after treatment (Fig. 1B). These results showed that AGEs inhibited the expression of hSR-BI/CLA-1 in HUVECs.

Figure 1
Figure 1

Effects of AGEs on the expression of hSR-BI/CLA-1 in HUVECs. (A) hSR-BI/CLA-1 protein expression in HUVECs treated with AGEs at varying concentration for 24 h. (B) hSR-BI/CLA-1 mRNA expression in HUVECs treated with AGEs at 100 μg/mL for varying time. Abundance of GAPDH or beta-actin served as control and is shown on the bottom of each lane, and the ratio of hSR-BI/CLA-1 to GAPDH/beta-actin is shown as percent of control in histogram. A histogram shows the mean ± s.e.m. (n = 3) of separate experiments for each group. *Significant difference (P < 0.05) compared to 0.

Citation: Journal of Molecular Endocrinology 66, 3; 10.1530/JME-20-0177

Effect of AGEs on hSR-BI/CLA-1 promoter activity

As a result of the aforementioned findings, we measured the transcriptional activity of the hSR-BI/CLA-1 promoter in HUVECs by assessing the effect of AGEs on pCLA-LUC activity. AGEs inhibited the activity of this promoter in a dose-dependent manner, consistent with the observed changes in the levels of hSR-BI/CLA-1 protein and mRNA. The maximum effect was observed at 100 μg/mL AGEs in HUVECs (Fig. 2).

Figure 2
Figure 2

AGEs decrease the promoter activity of hSR-BI/CLA-1. HSR-BI/CLA-1 promoter activity in HUVECs treated with AGEs at varying concentration for 24 h. Each data show the mean ± s.e.m. (n = 3) of separate transfections. *Significant difference (P < 0.05) compared to 0.

Citation: Journal of Molecular Endocrinology 66, 3; 10.1530/JME-20-0177

AGEs regulate hSR-BI/CLA-1 expression via its receptor RAGE

Previous studies have reported that RAGE is the main receptor for AGEs in endothelial cells (Ishibashi et al. 2013) and plays an important role in regulation ABCA1 expression in monocytes (Kumar et al. 2013). To investigate the role of RAGE in AGEs-regulated hSR-BI/CLA-1 expression, we employed the specific antibody, anti-RAGE antibody, to block the function of RAGE. As shown in Fig. 3A and B, anti-RAGE antibody attenuated the effect of AGEs on reduced the protein and mRNA level of hSR-BI/CLA-1. Consistently, the promoter activity of hSR-BI/CLA-1 was also rescued by blockade of RAGE (Fig. 3C), suggesting that RAGE is involved in AGEs-regulated hSR-BI/CLA-1 expression.

Figure 3
Figure 3

Blockade of RAGE rescues the effect of AGEs on hSR-BI/CLA-1 expression. (A and B) The protein and mRNA level of hSR-BI/CLA-1 in HUVECs treated with AGEs or AGEs plus anti-RAGE antibody for 24 h. (C) hSR-BI/CLA-1 promoter activity in HUVECs treated with AGEs or AGEs plus anti-RAGE antibody for 24 h. Each data shows the mean ± s.e.m. (n = 3) of separate transfections. *Significant difference (P < 0.05) compared to AGEs.

Citation: Journal of Molecular Endocrinology 66, 3; 10.1530/JME-20-0177

Transcriptional regulation of SR-BI/CLA-1 gene by AGEs-treatment

In terms of the transcriptional regulation of AGEs, several reports indicated that AGEs stimulation significantly activated the Smad1 signaling pathway to regulate the expression of several genes (Abe et al. 2004, Ohashi et al. 2004). In this case, we searched for a DNA motif within the hSR-BI/CLA-1 promoter to which Smad1 could bind. Examination of the promoter sequence revealed a 4-nt motif (GCCG) corresponding to the deduced Smad1 consensus binding sequence of the bone morphogenetic protein genes (Kusanagi et al. 2000). Figure 4 shows a schematic diagram of the GCCG-motif on the human and mouse SR-BI gene; the GCCG-motif is conserved between humans and mice. To investigate whether the binding of Smad1 to the GCCG-motif is required for its effect on the hSR-BI/CLA-1 promoter, we performed a chromatin immunoprecipitation assay to confirm Smad1 binding on the promoter. Figure 5A shows the PCR (PCR) amplification product, after the immunoprecipitation of the cross-linked chromatin with the Smad1 antibody (Fig. 5A, lane 1 and 2). Input served as a positive control, which used original sonicated chromatin as a PCR templet. No PCR amplified product was found after the immunoprecipitation of the cross-linked chromatin with negative control IgG (Fig. 5A, lane 4). The data supports our hypothesis that, Smad1 binds to the hSR-BI/CLA-1 promoter, which spans the nucleotides from −176 to −60 in the hSR-BI promoter sequence.

Figure 4
Figure 4

DNA analysis. An alignment shows the region around the Transcription Start Sites (TSS) of hSR-BI/CLA-1 conserved between human and mouse. A sequence of Smad1 binding sites is underlined. The numbers stand for the nucleotide site relative to the TSS of human.

Citation: Journal of Molecular Endocrinology 66, 3; 10.1530/JME-20-0177

Figure 5
Figure 5

AGEs mediate hSR-BI/CLA-1 transcription via transcription factor Smad1. (A) Binding of Smad1 to hSR-BI/CLA-1 promoter region. Smad1 specifically immunoprecipitates the hSR-BI/CLA-1 by ChIP assays. 0, no treatment; AGE, treatment with AGEs at 100 μg/mL; Input: original sonicated chromatin; NC, negative control IgG. (B) Transactivation through the 12xGCCG motif. Smad1 activity in HUVECs treated with AGEs at 100 μg/mL for 24 h. Each data show the mean ± s.e.m. (n = 3) of separate transfections. *Significant difference (P < 0.05) compared to control. (C) Effect of AGEs on hSR-BI/CLA-1 promoter or Smad1-responsive motif-mutated in hSR-BI/CLA-1 promoter activity. Each data shows the mean ± s.e.m. (n = 3) of separate transfections. *Significant difference (P < 0.05) compared to 0.

Citation: Journal of Molecular Endocrinology 66, 3; 10.1530/JME-20-0177

Smad1 mediated suppressive effect of AGE on hSR-BI/CLA-1 promoter activity

Next, we examined whether Smad1 participates in the suppression of hSR-BI/CLA-1 transcriptional activity by AGE. To detect the transcriptional activity of Smad1, induced by AGE, the 12xGCCG-Lux reporter gene system, constructed with the luciferase reporter gene inserted into twelves copies of the GCCG motif, was employed as described previously (Kusanagi et al. 2000). Figure 5B shows that AGE-treatment in HUVECs stimulated the activity of 12xGCCG-Lux compared to HUVECs without AGE treatment. This confirmed the hypothesis that AGE potentially regulates the genes responsible for the activation of Smad1 recruitment.

Smad1 suppressed hSR-BI/CLA-1 promoter activity

As Smad1 was found to be activated by AGEs-treatment in HUVECs, we hypothesized that activated Smad1 suppressed hSR-BI/CLA-1 promoter activity. We designed a plasmid construct, pCLA-mt-LUC, containing a mutated putative GCCG-motif (5′--157-3′ to 5′--150-3′). Transfection of HUVECs showed that AGEs failed to inhibit any luciferase activity in cells transfected with the pCLA-mt-LUC plasmid (Fig. 5C). However, as previously stated, it stimulated luciferase activity in cells transfected with the WT pCLA-LUC plasmid (Fig. 2). Together, these findings suggest that the putative GCCG-motif in the hSR-BI/CLA-1 promoter is involved in the AGEs-mediated inhibition of the hSR-BI/CLA-1 promoter.

Effect of AGEs on HDL-mediated eNOS phosphorylation

Previous studies have shown that HDL promotes the production of the atheroprotective signaling molecule NO in the endothelium (Yuhanna et al. 2001, Yu et al. 2007, Fukata et al. 2014). This process requires the high-affinity HDL receptor, hSR-BI/CLA-1; and is mediated by kinase cascades, that regulate the activity of eNOS by HDL-induced phosphorylation of eNOS at Ser 1179. As shown above, AGEs suppressed hSR-BI/CLA-1 protein expression and gene transcription. We examined the effect of AGEs on HDL-mediated eNOS activation in HUVECs. Without AGE treatment, HDL treatment enhanced the phosphorylation of eNOS at Ser 1179, similarly to a previous report (Fukata et al. 2014). Conversely, pretreatment with AGEs inhibited the phosphorylation of eNOS at Ser 1179 in HDL treated cells (Fig. 6).

Figure 6
Figure 6

Effect of AGEs on the activation of eNOS. AGEs decreased the activity of eNOS induced by HDL in HUVECs. 0, no treatment; AGE, treatment with AGEs at 100 μg/mL for 24 h; HDL, HDL at 10 μg/mL for 15 min; A+H, treatment with AGEs for 24 h and followed by HDL for 15 min. The ratio of Ser1177-eNOS to total eNOS is shown as percent of control. A graph showing the mean ± s.e.m. (n =3) of separate experiments for each treatment group is indicated. *Significant difference (P < 0.05) compared to 0 and #Significant difference (P < 0.05) compared to HDL.

Citation: Journal of Molecular Endocrinology 66, 3; 10.1530/JME-20-0177

Discussion

A decrease in the production of NO by eNOS is a risk factor for endothelial dysfunction, defined by impaired endothelium-dependent relaxation, and can cause symptoms such as hypertension, an early marker for atherosclerosis (Wang et al. 2008). Many risk factors of atherosclerosis, including dyslipidemia, hyperhomocysteinemia, and hyperglycemia, can decrease NO production and induce the pathogenesis of endothelial dysfunction (Xu et al. 2009). Several studies have shown that the phosphorylation of eNOS at serine 1177 plays an important role in the generation of NO in endothelial cells (Dimmeler et al. 1999, Fulton et al. 1999). Activation of kinases upstream of eNOS, such as Akt and AMP-activated protein kinase, increases the phosphorylation of eNOS and maintains endothelial function (Fulton et al. 1999). However, a detailed mechanism related to the transcriptional regulation of eNOS genes responsible for endothelial dysfunction remains largely unknown, limiting effective therapeutic interventions for atherosclerosis.

It is well known that HDL promotes the production of the atheroprotective signaling molecule, NO, in the endothelium (Gong et al. 2003, Murao et al. 2008b). The high-affinity HDL receptor, hSR-BI/CLA-1, is required for this process, which is mediated by kinase cascades that regulate the activity of eNOS. These kinases include Akt (also known as protein kinase B (PKB)), PKA, PKC, and calmodulin-dependent kinase II (Shaul & Mineo 2004). Previous work has shown that HDL stimulates the phosphorylation of eNOS at Ser1179, but not at Thr497 (Drew et al. 2004). Furthermore, the expression of Akt-DN decreases the effect of HDL on eNOS, thus, HDL-induced phosphorylation of eNOS is mediated by Akt kinase (Drew et al. 2004). We previously reported that the eNOS activation by HDL fluctuated in parallel with the upregulation or downregulation of endothelial SR-BI/CLA-1 expression (Yu et al. 2007, Fukata et al. 2014). In this study, we show that inhibition of SR-BI/CLA-1 gene expression by AGEs decreased eNOS phosphorylation by HDL. As shown in Fig. 1A, AGEs at 100 μg/mL reduced the protein expression of hSR-BI/CLA-1 to (27.6 ± 4.3)% of control. As shown in Fig. 6, HDL stimulation activated eNOS phosphorylation to (177.6 ± 24.4)% of no stimulation. Phosphorylation of eNOS in the group of AGEs plus HDL was (90.3 ± 5.9)% of no stimulation. Thus, treatment with AGEs at 100 μg/mL resulted in about 60% reduction of hSR-BI/CLA-1 expression and about 50% reduction of HDL-stimulated eNOS activation. Further studies will be needed to clarify the association between the decreased hSR-BI/CLA-1 by AGEs and the AGEs-induced decrease in HDL-mediated eNOS activation. In terms of the mechanism of eNOS activation by hSR-BI/CLA-1, the C-terminal tail of hSR-BI/CLA-1 potentially plays an important role in HDL-mediated signal transduction mechanisms, including the PI3K/Akt signaling pathway (Cao et al. 2004). We speculate that the coupling might involve intermediary proteins such as CLAMP, a protein containing four PDZ domains that associate with the extreme C terminus of SR-BI (Silver 2002).

Diabetes enhances the accumulation of AGEs through the glycation of proteins, thereby altering enzymatic activity, disrupting molecular conformation, and interfering with receptor function. AGEs create cross-links with proteins, lipids, and nucleic acids; first accumulating extracellularly through the basement membrane, and then intracellularly, leading to the development of diabetic complications (Yan et al. 2008). RAGE is identified as the main receptor of AGEs in endothelial cells and ligation of RAGE has been demonstrated to protect cells against AGEs (Ishibashi et al. 2013, Kumar et al. 2013). In this study, we used RAGE specific antibody to block the function of RAGE and it attenuated the effect of AGEs on hSR-BI/CLA-1 expression. Interaction between AGEs and their receptor (RAGE) increases both, mitochondrial and NAD phosphate (NADPH) oxidase-dependent generation of reactive oxygen species (ROS). Excessive ROS is cytotoxic and contributes to thrombosis, vascular inflammation, and diabetic vascular complications (Yan et al. 2008). Moreover, the activation of RAGE induces various pro-inflammatory mediators in endothelial cells, such as, monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1, and transforming growth factor beta 1 (TGF-β1) (Goumans et al. 2002). As a member of TGF-β family receptor, activin receptor-like kinase-1 (ALK-1) interacts with four ligands: TGF-β1 and TGF-β3, in a complex with the receptor type II (TβRII); and with bone morphogenetic protein 9 (BMP-9) and BMP-10, in a complex with the activin receptor type IIA, or the BMP receptor type II. ALK-1 activation induces phosphorylation of Smad1/5/8, which in turn dimerizes with Smad4, and this complex is translocated to the nucleus and directly regulates transcription of specific genes (Massague 2000). Previously, Abe et al. identified that Smad1 could directly bind to alpha 1 type IV collagen (Col4) promoter and this binding mediated in AGEs-regulated Col4 gene expression (Abe et al. 2004). Further, Smad1 was significantly induced in AGE-treated mesangial cells (Ohashi et al. 2004).

ALK-1 and Smad1 is also expressed in endothelial cells. In this study, we showed that AGEs induced Smad1 activity, and confirmed the binding of Smad1 on the hSR-BI/CLA-1 promoter in response to AGEs-treatment.

One of the aims of this study was to investigate the signal transduction pathways activated by AGEs in HUVECs. We reported that the Smad1 pathway regulated the promoter activity of hSR-BI/CLA-1. SR-BI/CLA-1 is an 82-kDa membrane glycoprotein that serves as receptor of HDL and plays an essential role in reverse cholesterol transport (Acton et al. 1996, Murao et al. 1997). SR-BI/CLA-1 gene expression is mainly exerted at the transcription level. The promoters of the human and rat SR-BI genes contain DNA sequences that bind several positively acting transcription factors in response to exogenous or endogenous stimuli. Hormone nuclear receptors, such as the peroxisome proliferator activated receptor α (PPARα) and the liver X receptors α and β (LXRα, LXRβ), positively regulate the expression of the human SR-BI gene in response to fibrates and oxysterols, respectively (Malerød et al. 2002, Lopez & McLean 2006). The estrogen receptors α and β (ERα and β) could bind to three different estrogen-responsive elements on the rat SR-BI promoter and regulate its activity in response to estrogens (Lopez et al. 2002). In addition, the SR-BI promoter is also regulated by negatively acting factors. The Yin Yang-1 (YY-1) transcription factor was proved to repress the activity of the SR-BI promoter by inhibiting the binding of the sterol-responsive element binding-protein (SREBP)-1a (Shea-Eaton et al. 2001).

We previously reported that the p38MAPK/Sp1 response to hyperglycemia is the negative acting transcriptional factor for the hSR-BI/CLA-1 gene (Murao et al. 2008c); further, in this present study, we identified that Smad1 might be similar to this. Recent report demonstrated that activation of Smad signaling could directly mediate PPAR gene transcription to contribute TGF-β-repressed PPAR expression (Lakshmi et al. 2017). Thus, detailed mechanism under Smad1-regulated hSR-BI/CLA-1 transcription needs to be further studied.

The rapid increase of diabetic patients has caused diabetes mellitus (DM) to be a serious medical problem worldwide. Vascular complications are the main cause of morbidity and mortality in diabetic patients, these complications mostly result from endothelial dysfunction and vascular inflammation (Yan et al. 2008). Many studies have revealed that AGEs play a critical role in promoting diabetic vascular dysfunction and diabetes development (Hartge et al. 2007, Orasanu & Plutzky 2009). In this study, we found that AGEs induced transcriptional activity of Smad1, and decreased HDL-dependent eNOS activation, suggesting that Smad1 has therapeutic value in the treatment of diseases, such as endothelial dysfunction, in which AGEs play an important role.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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  • Fukata Y, Yu X, Imachi H, Nishiuchi T, Lyu J, Seo K, Takeuchi A, Iwama H, Masugata H & Hoshikawa H et al.2014 17β-Estradiol regulates scavenger receptor class BI gene expression via protein kinase C in vascular endothelial cells. Endocrine 46 644650. (https://doi.org/10.1007/s12020-013-0134-5)

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  • Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A & Sessa WC 1999 Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399 597601. (https://doi.org/10.1038/21218)

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  • Glomset JA 1968 The plasma lecithins:cholesterol acyltransferase reaction. Journal of Lipid Research 9 155167. (https://doi.org/10.1016/S0022-2275(2043114-1)

    • Search Google Scholar
    • Export Citation
  • Gong M, Wilson M, Kelly T, Su W, Dressman J, Kincer J, Matveev SV, Guo L, Guerin T & Li XA et al.2003 HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI-dependent manner. Journal of Clinical Investigation 111 15791587. (https://doi.org/10.1172/JCI16777)

    • Search Google Scholar
    • Export Citation
  • Goumans M-J, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P & Dijke P 2002 Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO Journal 21 1743–1753. (doi: 10.1093/emboj/21.7.1743)

    • Search Google Scholar
    • Export Citation
  • Hartge MM, Unger T & Kintscher U 2007 The endothelium and vascular inflammation in diabetes. Diabetes and Vascular Disease Research 4 8488. (https://doi.org/10.3132/dvdr.2007.025)

    • Search Google Scholar
    • Export Citation
  • Imachi H, Murao K, Cao W, Tada S, Taminato T, Wong NCW, Takahara J & Ishida T 2003 Expression of human scavenger receptor B1 on and in human platelets. Arteriosclerosis, Thrombosis, and Vascular Biology 23 898904. (https://doi.org/10.1161/01.ATV.0000067429.46333.7B)

    • Search Google Scholar
    • Export Citation
  • Ishibashi Y, Matsui T, Maeda S, Higashimoto Y & Yamagishi S 2013 Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor. Cardiovascular Diabetology 12 125. (https://doi.org/10.1186/1475-2840-12-125)

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    • Export Citation
  • Kumar P, Raghavan S, Shanmugam G & Shanmugam N 2013 Ligation of RAGE with ligand S100B attenuates ABCA1 expression in monocytes. Metabolism: Clinical and Experimental 62 11491158. (https://doi.org/10.1016/j.metabol.2013.02.006)

    • Search Google Scholar
    • Export Citation
  • Kusanagi K, Inoue H, Ishidou Y, Mishima HK, Kawabata M & Miyazono K 2000 Characterization of a bone morphogenetic protein-responsive Smad-binding element. Molecular Biology of the Cell 11 555565. (https://doi.org/10.1091/mbc.11.2.555)

    • Search Google Scholar
    • Export Citation
  • Lakshmi SP, Reddy AT & Reddy RC 2017 Transforming growth factor beta suppresses peroxisome proliferator-activated receptor gamma expression via both SMAD binding and novel TGF-beta inhibitory elements. Biochemical Journal 474 15311546. (https://doi.org/10.1042/BCJ20160943)

    • Search Google Scholar
    • Export Citation
  • Lopez D & McLean MP 2006 Activation of the rat scavenger receptor class B type I gene by PPARalpha. Molecular and Cellular Endocrinology 251 6777. (https://doi.org/10.1016/j.mce.2006.02.011)

    • Search Google Scholar
    • Export Citation
  • Lopez D, Sanchez MD, Shea-Eaton W & McLean MP 2002 Estrogen activates the high-density lipoprotein receptor gene via binding to estrogen response elements and interaction with sterol regulatory element binding protein-1A. Endocrinology 143 21552168. (https://doi.org/10.1210/endo.143.6.8855)

    • Search Google Scholar
    • Export Citation
  • Malerød L, Juvet LK, Hanssen-Bauer A, Eskild W & Berg T 2002 Oxysterol-activated LXRalpha/RXR induces hSR-BI-promoter activity in hepatoma cells and preadipocytes. Biochemical and Biophysical Research Communications 299 916923. (https://doi.org/10.1016/s0006-291x(0202760-2)

    • Search Google Scholar
    • Export Citation
  • Massague J 2000 How cells read TGF-beta signals. Nature Reviews: Molecular Cell Biology 1 169178. (https://doi.org/10.1038/35043051)

  • Murao K, Terpstra V, Green SR, Kondratenko N, Steinberg D & Quehenberger O 1997 Characterization of CLA-1, a human homologue of rodent scavenger receptor BI, as a receptor for high density lipoprotein and apoptotic thymocytes. Journal of Biological Chemistry 272 1755117557. (https://doi.org/10.1074/jbc.272.28.17551)

    • Search Google Scholar
    • Export Citation
  • Murao K, Imachi H, Yu X, Cao WM, Muraoka T, Dobashi H, Hosomi N, Haba R, Iwama H & Ishida T 2008a The transcriptional factor prolactin regulatory element-binding protein mediates the gene transcription of adrenal scavenger receptor class B type I via 3′,5′-cyclic adenosine 5′-monophosphate. Endocrinology 149 61036112. (https://doi.org/10.1210/en.2008-0380)

    • Search Google Scholar
    • Export Citation
  • Murao K, Imachi H, Yu X, Cao WM, Nishiuchi T, Chen K, Li J, Ahmed RA, Wong NC & Ishida T 2008b Interferon alpha decreases expression of human scavenger receptor class BI, a possible HCV receptor in hepatocytes. Gut 57 664671. (https://doi.org/10.1136/gut.2006.111443)

    • Search Google Scholar
    • Export Citation
  • Murao K, Yu X, Imachi H, Cao WM, Chen K, Matsumoto K, Nishiuchi T, Wong NC & Ishida T 2008c Hyperglycemia suppresses hepatic scavenger receptor class B type I expression. American Journal of Physiology: Endocrinology and Metabolism 294 E78E87. (https://doi.org/10.1152/ajpendo.00023.2007)

    • Search Google Scholar
    • Export Citation
  • Nin JW, Jorsal A, Ferreira I, Schalkwijk CG, Prins MH, Parving HH, Tarnow L, Rossing P & Stehouwer CD 2011 Higher plasma levels of advanced glycation end products are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12-year follow-up study. Diabetes Care 34 442447. (https://doi.org/10.2337/dc10-1087)

    • Search Google Scholar
    • Export Citation
  • Ohashi S, Abe H, Takahashi T, Yamamoto Y, Takeuchi M, Arai H, Nagata K, Kita T, Okamoto H & Yamamoto H et al.2004 Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy. Journal of Biological Chemistry 279 1981619823. (https://doi.org/10.1074/jbc.M310428200)

    • Search Google Scholar
    • Export Citation
  • Orasanu G & Plutzky J 2009 The pathologic continuum of diabetic vascular disease. Journal of the American College of Cardiology 53 (Supplement 5) S35S42. (https://doi.org/10.1016/j.jacc.2008.09.055)

    • Search Google Scholar
    • Export Citation
  • Pedrinelli R, Giampietro O, Carmassi F, Melillo E, Dell’Omo G, Catapano G, Matteucci E, Talarico L, Morale M & De Negri F 1994 Microalbuminuria and endothelial dysfunction in essential hypertension. Lancet 344 1418. (https://doi.org/10.1016/s0140-6736(9491047-2)

    • Search Google Scholar
    • Export Citation
  • Pruitt KD, Tatusova T & Maglott DR 2005 NCBI reference sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Research 33 D501D504. (https://doi.org/10.1093/nar/gki025)

    • Search Google Scholar
    • Export Citation
  • Rao Kondapally Seshasai S, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, Whincup PH, Mukamal KJ, Gillum RF & Holme I et al.2011 Diabetes mellitus, fasting glucose, and risk of cause-specific death. New England Journal of Medicine 364 829841. (https://doi.org/10.1056/NEJMoa1008862)

    • Search Google Scholar
    • Export Citation
  • Schwartz S, Kent WJ, Smit A, Zhang Z, Baertsch R, Hardison RC, Haussler D & Miller W 2003 Human-mouse alignments with BLASTZ. Genome Research 13 103107. (https://doi.org/10.1101/gr.809403)

    • Search Google Scholar
    • Export Citation
  • Shaul PW & Mineo C 2004 HDL action on the vascular wall: is the answer NO? Journal of Clinical Investigation 113 509513. (https://doi.org/10.1172/JCI21072)

    • Search Google Scholar
    • Export Citation
  • Shea-Eaton W, Lopez D & McLean MP 2001 Yin Yang 1 protein negatively regulates high-density lipoprotein receptor gene transcription by disrupting binding of sterol regulatory element binding protein to the sterol regulatory element. Endocrinology 142 4958. (https://doi.org/10.1210/endo.142.1.7868)

    • Search Google Scholar
    • Export Citation
  • Silver DL 2002 A carboxyl-terminal PDZ-interacting domain of scavenger receptor B, type I is essential for cell surface expression in liver. Journal of Biological Chemistry 277 3404234047. (https://doi.org/10.1074/jbc.M206584200)

    • Search Google Scholar
    • Export Citation
  • Soro-Paavonen A, Zhang WZ, Venardos K, Coughlan MT, Harris E, Tong DC, Brasacchio D, Paavonen K, Chin-Dusting J & Cooper ME et al.2010 Advanced glycation end-products induce vascular dysfunction via resistance to nitric oxide and suppression of endothelial nitric oxide synthase. Journal of Hypertension 28 780788. (https://doi.org/10.1097/HJH.0b013e328335043e)

    • Search Google Scholar
    • Export Citation
  • Stirban A, Negrean M, Stratmann B, Gawlowski T, Horstmann T, Gotting C, Kleesiek K, Mueller Roesel M, Koschinsky T & Uribarri J et al.2006 Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care 29 20642071. (https://doi.org/10.2337/dc06-0531)

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  • Xu J, Wang S, Wu Y, Song P & Zou MH 2009 Tyrosine nitration of PA700 activates the 26S proteasome to induce endothelial dysfunction in mice with angiotensin II-induced hypertension. Hypertension 54 625632. (https://doi.org/10.1161/HYPERTENSIONAHA.109.133736)

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  • Yu X, Murao K, Imachi H, Cao WM, Li J, Matsumoto K, Nishiuchi T, Ahmed RA, Wong NC & Kosaka H et al.2007 Regulation of scavenger receptor class BI gene expression by angiotensin II in vascular endothelial cells. Hypertension 49 13781384. (https://doi.org/10.1161/HYPERTENSIONAHA.106.082479)

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  • Yuhanna IS, Zhu Y, Cox BE, Hahner LD, Osborne-Lawrence S, Lu P, Marcel YL, Anderson RG, Mendelsohn ME & Hobbs HH et al.2001 High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase. Nature Medicine 7 853857. (https://doi.org/10.1038/89986)

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    Effects of AGEs on the expression of hSR-BI/CLA-1 in HUVECs. (A) hSR-BI/CLA-1 protein expression in HUVECs treated with AGEs at varying concentration for 24 h. (B) hSR-BI/CLA-1 mRNA expression in HUVECs treated with AGEs at 100 μg/mL for varying time. Abundance of GAPDH or beta-actin served as control and is shown on the bottom of each lane, and the ratio of hSR-BI/CLA-1 to GAPDH/beta-actin is shown as percent of control in histogram. A histogram shows the mean ± s.e.m. (n = 3) of separate experiments for each group. *Significant difference (P < 0.05) compared to 0.

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    AGEs decrease the promoter activity of hSR-BI/CLA-1. HSR-BI/CLA-1 promoter activity in HUVECs treated with AGEs at varying concentration for 24 h. Each data show the mean ± s.e.m. (n = 3) of separate transfections. *Significant difference (P < 0.05) compared to 0.

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    Blockade of RAGE rescues the effect of AGEs on hSR-BI/CLA-1 expression. (A and B) The protein and mRNA level of hSR-BI/CLA-1 in HUVECs treated with AGEs or AGEs plus anti-RAGE antibody for 24 h. (C) hSR-BI/CLA-1 promoter activity in HUVECs treated with AGEs or AGEs plus anti-RAGE antibody for 24 h. Each data shows the mean ± s.e.m. (n = 3) of separate transfections. *Significant difference (P < 0.05) compared to AGEs.

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    DNA analysis. An alignment shows the region around the Transcription Start Sites (TSS) of hSR-BI/CLA-1 conserved between human and mouse. A sequence of Smad1 binding sites is underlined. The numbers stand for the nucleotide site relative to the TSS of human.

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    AGEs mediate hSR-BI/CLA-1 transcription via transcription factor Smad1. (A) Binding of Smad1 to hSR-BI/CLA-1 promoter region. Smad1 specifically immunoprecipitates the hSR-BI/CLA-1 by ChIP assays. 0, no treatment; AGE, treatment with AGEs at 100 μg/mL; Input: original sonicated chromatin; NC, negative control IgG. (B) Transactivation through the 12xGCCG motif. Smad1 activity in HUVECs treated with AGEs at 100 μg/mL for 24 h. Each data show the mean ± s.e.m. (n = 3) of separate transfections. *Significant difference (P < 0.05) compared to control. (C) Effect of AGEs on hSR-BI/CLA-1 promoter or Smad1-responsive motif-mutated in hSR-BI/CLA-1 promoter activity. Each data shows the mean ± s.e.m. (n = 3) of separate transfections. *Significant difference (P < 0.05) compared to 0.

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    Effect of AGEs on the activation of eNOS. AGEs decreased the activity of eNOS induced by HDL in HUVECs. 0, no treatment; AGE, treatment with AGEs at 100 μg/mL for 24 h; HDL, HDL at 10 μg/mL for 15 min; A+H, treatment with AGEs for 24 h and followed by HDL for 15 min. The ratio of Ser1177-eNOS to total eNOS is shown as percent of control. A graph showing the mean ± s.e.m. (n =3) of separate experiments for each treatment group is indicated. *Significant difference (P < 0.05) compared to 0 and #Significant difference (P < 0.05) compared to HDL.

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  • Cao WM, Murao K, Imachi H, Yu X, Abe H, Yamauchi A, Niimi M, Miyauchi A, Wong NC & Ishida T 2004 A mutant high-density lipoprotein receptor inhibits proliferation of human breast cancer cells. Cancer Research 64 15151521. (https://doi.org/10.1158/0008-5472.can-03-0675)

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  • Fukata Y, Yu X, Imachi H, Nishiuchi T, Lyu J, Seo K, Takeuchi A, Iwama H, Masugata H & Hoshikawa H et al.2014 17β-Estradiol regulates scavenger receptor class BI gene expression via protein kinase C in vascular endothelial cells. Endocrine 46 644650. (https://doi.org/10.1007/s12020-013-0134-5)

    • Search Google Scholar
    • Export Citation
  • Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A & Sessa WC 1999 Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399 597601. (https://doi.org/10.1038/21218)

    • Search Google Scholar
    • Export Citation
  • Glomset JA 1968 The plasma lecithins:cholesterol acyltransferase reaction. Journal of Lipid Research 9 155167. (https://doi.org/10.1016/S0022-2275(2043114-1)

    • Search Google Scholar
    • Export Citation
  • Gong M, Wilson M, Kelly T, Su W, Dressman J, Kincer J, Matveev SV, Guo L, Guerin T & Li XA et al.2003 HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI-dependent manner. Journal of Clinical Investigation 111 15791587. (https://doi.org/10.1172/JCI16777)

    • Search Google Scholar
    • Export Citation
  • Goumans M-J, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P & Dijke P 2002 Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO Journal 21 1743–1753. (doi: 10.1093/emboj/21.7.1743)

    • Search Google Scholar
    • Export Citation
  • Hartge MM, Unger T & Kintscher U 2007 The endothelium and vascular inflammation in diabetes. Diabetes and Vascular Disease Research 4 8488. (https://doi.org/10.3132/dvdr.2007.025)

    • Search Google Scholar
    • Export Citation
  • Imachi H, Murao K, Cao W, Tada S, Taminato T, Wong NCW, Takahara J & Ishida T 2003 Expression of human scavenger receptor B1 on and in human platelets. Arteriosclerosis, Thrombosis, and Vascular Biology 23 898904. (https://doi.org/10.1161/01.ATV.0000067429.46333.7B)

    • Search Google Scholar
    • Export Citation
  • Ishibashi Y, Matsui T, Maeda S, Higashimoto Y & Yamagishi S 2013 Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor. Cardiovascular Diabetology 12 125. (https://doi.org/10.1186/1475-2840-12-125)

    • Search Google Scholar
    • Export Citation
  • Kumar P, Raghavan S, Shanmugam G & Shanmugam N 2013 Ligation of RAGE with ligand S100B attenuates ABCA1 expression in monocytes. Metabolism: Clinical and Experimental 62 11491158. (https://doi.org/10.1016/j.metabol.2013.02.006)

    • Search Google Scholar
    • Export Citation
  • Kusanagi K, Inoue H, Ishidou Y, Mishima HK, Kawabata M & Miyazono K 2000 Characterization of a bone morphogenetic protein-responsive Smad-binding element. Molecular Biology of the Cell 11 555565. (https://doi.org/10.1091/mbc.11.2.555)

    • Search Google Scholar
    • Export Citation
  • Lakshmi SP, Reddy AT & Reddy RC 2017 Transforming growth factor beta suppresses peroxisome proliferator-activated receptor gamma expression via both SMAD binding and novel TGF-beta inhibitory elements. Biochemical Journal 474 15311546. (https://doi.org/10.1042/BCJ20160943)

    • Search Google Scholar
    • Export Citation
  • Lopez D & McLean MP 2006 Activation of the rat scavenger receptor class B type I gene by PPARalpha. Molecular and Cellular Endocrinology 251 6777. (https://doi.org/10.1016/j.mce.2006.02.011)

    • Search Google Scholar
    • Export Citation
  • Lopez D, Sanchez MD, Shea-Eaton W & McLean MP 2002 Estrogen activates the high-density lipoprotein receptor gene via binding to estrogen response elements and interaction with sterol regulatory element binding protein-1A. Endocrinology 143 21552168. (https://doi.org/10.1210/endo.143.6.8855)

    • Search Google Scholar
    • Export Citation
  • Malerød L, Juvet LK, Hanssen-Bauer A, Eskild W & Berg T 2002 Oxysterol-activated LXRalpha/RXR induces hSR-BI-promoter activity in hepatoma cells and preadipocytes. Biochemical and Biophysical Research Communications 299 916923. (https://doi.org/10.1016/s0006-291x(0202760-2)

    • Search Google Scholar
    • Export Citation
  • Massague J 2000 How cells read TGF-beta signals. Nature Reviews: Molecular Cell Biology 1 169178. (https://doi.org/10.1038/35043051)

  • Murao K, Terpstra V, Green SR, Kondratenko N, Steinberg D & Quehenberger O 1997 Characterization of CLA-1, a human homologue of rodent scavenger receptor BI, as a receptor for high density lipoprotein and apoptotic thymocytes. Journal of Biological Chemistry 272 1755117557. (https://doi.org/10.1074/jbc.272.28.17551)

    • Search Google Scholar
    • Export Citation
  • Murao K, Imachi H, Yu X, Cao WM, Muraoka T, Dobashi H, Hosomi N, Haba R, Iwama H & Ishida T 2008a The transcriptional factor prolactin regulatory element-binding protein mediates the gene transcription of adrenal scavenger receptor class B type I via 3′,5′-cyclic adenosine 5′-monophosphate. Endocrinology 149 61036112. (https://doi.org/10.1210/en.2008-0380)

    • Search Google Scholar
    • Export Citation
  • Murao K, Imachi H, Yu X, Cao WM, Nishiuchi T, Chen K, Li J, Ahmed RA, Wong NC & Ishida T 2008b Interferon alpha decreases expression of human scavenger receptor class BI, a possible HCV receptor in hepatocytes. Gut 57 664671. (https://doi.org/10.1136/gut.2006.111443)

    • Search Google Scholar
    • Export Citation
  • Murao K, Yu X, Imachi H, Cao WM, Chen K, Matsumoto K, Nishiuchi T, Wong NC & Ishida T 2008c Hyperglycemia suppresses hepatic scavenger receptor class B type I expression. American Journal of Physiology: Endocrinology and Metabolism 294 E78E87. (https://doi.org/10.1152/ajpendo.00023.2007)

    • Search Google Scholar
    • Export Citation
  • Nin JW, Jorsal A, Ferreira I, Schalkwijk CG, Prins MH, Parving HH, Tarnow L, Rossing P & Stehouwer CD 2011 Higher plasma levels of advanced glycation end products are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12-year follow-up study. Diabetes Care 34 442447. (https://doi.org/10.2337/dc10-1087)

    • Search Google Scholar
    • Export Citation
  • Ohashi S, Abe H, Takahashi T, Yamamoto Y, Takeuchi M, Arai H, Nagata K, Kita T, Okamoto H & Yamamoto H et al.2004 Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy. Journal of Biological Chemistry 279 1981619823. (https://doi.org/10.1074/jbc.M310428200)

    • Search Google Scholar
    • Export Citation
  • Orasanu G & Plutzky J 2009 The pathologic continuum of diabetic vascular disease. Journal of the American College of Cardiology 53 (Supplement 5) S35S42. (https://doi.org/10.1016/j.jacc.2008.09.055)

    • Search Google Scholar
    • Export Citation
  • Pedrinelli R, Giampietro O, Carmassi F, Melillo E, Dell’Omo G, Catapano G, Matteucci E, Talarico L, Morale M & De Negri F 1994 Microalbuminuria and endothelial dysfunction in essential hypertension. Lancet 344 1418. (https://doi.org/10.1016/s0140-6736(9491047-2)

    • Search Google Scholar
    • Export Citation
  • Pruitt KD, Tatusova T & Maglott DR 2005 NCBI reference sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Research 33 D501D504. (https://doi.org/10.1093/nar/gki025)

    • Search Google Scholar
    • Export Citation
  • Rao Kondapally Seshasai S, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, Whincup PH, Mukamal KJ, Gillum RF & Holme I et al.2011 Diabetes mellitus, fasting glucose, and risk of cause-specific death. New England Journal of Medicine 364 829841. (https://doi.org/10.1056/NEJMoa1008862)

    • Search Google Scholar
    • Export Citation
  • Schwartz S, Kent WJ, Smit A, Zhang Z, Baertsch R, Hardison RC, Haussler D & Miller W 2003 Human-mouse alignments with BLASTZ. Genome Research 13 103107. (https://doi.org/10.1101/gr.809403)

    • Search Google Scholar
    • Export Citation
  • Shaul PW & Mineo C 2004 HDL action on the vascular wall: is the answer NO? Journal of Clinical Investigation 113 509513. (https://doi.org/10.1172/JCI21072)

    • Search Google Scholar
    • Export Citation
  • Shea-Eaton W, Lopez D & McLean MP 2001 Yin Yang 1 protein negatively regulates high-density lipoprotein receptor gene transcription by disrupting binding of sterol regulatory element binding protein to the sterol regulatory element. Endocrinology 142 4958. (https://doi.org/10.1210/endo.142.1.7868)

    • Search Google Scholar
    • Export Citation
  • Silver DL 2002 A carboxyl-terminal PDZ-interacting domain of scavenger receptor B, type I is essential for cell surface expression in liver. Journal of Biological Chemistry 277 3404234047. (https://doi.org/10.1074/jbc.M206584200)

    • Search Google Scholar
    • Export Citation
  • Soro-Paavonen A, Zhang WZ, Venardos K, Coughlan MT, Harris E, Tong DC, Brasacchio D, Paavonen K, Chin-Dusting J & Cooper ME et al.2010 Advanced glycation end-products induce vascular dysfunction via resistance to nitric oxide and suppression of endothelial nitric oxide synthase. Journal of Hypertension 28 780788. (https://doi.org/10.1097/HJH.0b013e328335043e)

    • Search Google Scholar
    • Export Citation
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