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CARDIOVASCULAR
Down-Regulates Receptor for Advanced Glycation End Products and Inhibits Smooth Muscle Cell Proliferation in a Diabetic and Nondiabetic Rat Carotid Artery Injury Model
Departments of Cardiovascular Medicine and Cell Biology, Cleveland Clinic Foundation, Cleveland, Ohio (K.W., Z.Z., M.Z., L.F., F.F., X.Z., A.M.L., E.J.T., M.S.P.); and Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York (W.Q., A.M.S.)
Received for publication
September 2, 2005
Accepted
December 19, 2005.
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Abstract |
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(PPAR), which inhibits neointimal hyperplasia, has been shown to decrease RAGE expression in cultured endothelial cells. We hypothesized that PPAR agonists inhibit neointimal hyperplasia via down-regulation of RAGE in vivo. Pretreatment of rat aortic smooth muscle cells (SMCs) with PPAR agonist rosiglitazone significantly down-regulated RAGE expression and inhibited SMC proliferation in response to the RAGE agonist S100/calgranulins. In vivo studies showed that rosiglitazone decreased RAGE expression and SMC proliferation at 7 days following carotid arterial injury in both diabetic and nondiabetic rats. At 21 days following injury, neointimal formation was significantly decreased in both diabetic and nondiabetic animals that received rosiglitazone. To determine whether inhibition of neointimal formation by PPAR activation could fully be accounted for by its down-regulation of RAGE, we compared the results obtained in animals treated with sRAGE, PPAR activator, and sRAGE + PPAR activator. Consistent with PPAR working through its effects on RAGE, we found that the addition of PPAR activator to sRAGE did not result in any further decrease in neointimal formation. These data demonstrate for the first time that PPAR agonists inhibit RAGE expression at sites of arterial injury and suggest that down-regulation of RAGE by the PPAR activation inhibits neointimal formation in response to arterial injury.
; Park et al., 2001; Zhou et al., 2002, 2003). This link between inflammation, restenosis, and diabetes highlights the potential therapeutic application of anti-inflammatory compounds to inhibit restenosis, especially in diabetic patients.
Peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors. PPAR is expressed in all vascular cells, including vascular SMCs (VSMCs), endothelial cells, and monocyte/macrophage (Marx et al., 1998a,b; Ricote et al., 1998a; Law et al., 2000). Thiazolidinediones (TZDs), a class of drugs that are high-affinity ligands for PPAR are currently being used clinically for their insulin-sensitizing activity. PPAR agonists have been shown to have anti-inflammatory properties (Jiang et al., 1998; Ricote et al., 1998b) and to inhibit vascular remodeling late following arterial injury (Law et al., 1996; Igarashi et al., 1997; Goetze et al., 1999; Yoshimoto et al., 1999). In particular, TZDs have been reported to inhibit cytokine-mediated endothelial cell proliferation (Gralinski et al., 1998), suppress endothelin-1 secretion from vascular endothelial cells (Delerive et al., 1999), and enhance cytokine-induced SMC apoptosis (Aizawa et al., 2001). It has also been shown that TZDs inhibit VSMCs proliferation and migration (Law et al., 1996, 2000; Marx et al., 1998a,b; Li et al., 2000). All of these properties suggest that PPAR ligands may influence growth of vascular cells (Rosen and Spiegelman, 2000).
We have demonstrated recently (Zhou et al., 2003) that inhibiting binding of ligands for the receptor for advanced glycosylation end products (RAGE) by soluble RAGE (sRAGE), a soluble portion of the extracellular domain of RAGE, significantly attenuates neointimal formation following arterial injury in diabetic and nondiabetic rat models. TZDs have been recently shown to decrease human endothelial cell RAGE mRNA expression (Marx et al., 2004). However, the effect of PPAR activation on RAGE expression in VSMC is still unknown. Based on our previous results with sRAGE, we wanted to test whether TZDs inhibited RAGE expression in SMC in vitro and in vivo and hypothesized that PPAR agonists could lead to a decrease in neointimal formation following arterial injury through the down-regulation of RAGE.
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Materials and Methods |
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) and seeded into 12-well plates (1.2 x 104 cells/well) in routine Dulbecco's modified Eagle's medium with 10% fetal bovine serum for 48 h, and the culture medium was replaced by Dulbecco's modified Eagle's medium without fetal bovine serum for 24 h. Rosiglitazone was added 2 h before the addition of S100 protein (Calbiochem, San Diego, CA). In one group, both rosiglitazone (10 µm/l) and sRAGE (40 µg/ml) were added before the stimulation of VSMCs. For all data shown, each individual experiment represents an independent preparation of VSMCs Measurement of VSMCs Proliferation. VSMCs were incubated with 2 µM S100 and simultaneously by incremental concentration of rosiglitazone (1, 5, and 10 µM) for 24 h. Cells were harvested, and cell number was determined using a Coulter cell counter.
Surgical Procedures. The Zucker obese and lean rats (Genetic Models, Inc./Charles River Laboratories, Inc., Wilmington, MA) aged 9 to 12 weeks were used in this study. All experiments conformed to the position of American Heart Association on research animal use and care and were conducted with the approval of Animal Research Committee of the Cleveland Clinic Foundation. Carotid artery injury was induced exactly as described previously (Zhou et al., 2002, 2003). Briefly, carotid artery injury was induced by balloon de-endothelialization. After induction of anesthesia, a midline cervical incision was made to expose the left external carotid artery. The external carotid artery was ligated, and the internal carotid artery was temporarily ligated. A 2F Fogarty balloon catheter (Baxter Healthcare Corp., Deerfield, IL) was introduced. The catheter was passed into the aortic arch, and the balloon was distended with saline until a slight resistance was felt on slight traction. After withdrawal into the common carotid artery, the balloon was rotated while pulling back through the common carotid artery. This procedure was repeated three times.
Administration of PPAR Activator and sRAGE. Rosiglitazone (8 mg/kg/day), a TZD with high affinity for PPAR, was administered by gavage 7 days before injury and continued until day 4, 7, and 21 after injury according to different groups. Based on our previous study (Zhou et al., 2003), murine sRAGE (0.5 mg/day) was administered intraperitoneally beginning 1 day before and continued until day 6 after injury.
Tissue Harvest and Preparation. The animals were sacrificed at 4, 7, and 21 days after injury. For animals sacrificed at day 7 and 21, the injured vessel segments were either perfusion-fixed with 5% HISTOCHOICE (AMRESCO Inc., Solon, OH) at 120 mm Hg and embedded in paraffin for later morphometric and immunohistochemistry assay or snap-frozen in liquid nitrogen for later PCR analysis.
Morphometry. The fixed carotid arteries were cut in serial sections, at 5 mm apart and stained with H&E and elastic-Van Gieson stain. An observer blinded to the study groups performed morphometric analyses using computerized digital microscopic planimetry software (Image-Pro Plus; Media Cybernetics, Inc., Silver Spring, MD). The section from four to five sections from each injured arterial segment exhibiting the most severe degree of luminal narrowing was assessed as the "lesion" point. The neointimal and medial boundaries were determined, and the luminal, internal elastic lamina, and the external elastic lamina areas were measured, and the ratio of intimal and medial area was calculated.
Immunohistochemistry. For the vessel segments harvested 7 days after injury, immunohistochemistry was performed to determine whether rosiglitazone treatment down-regulates the RAGE expression. Briefly, RAGE was identified by a specific antibody against it (Santa Cruz Biotechnology, Inc., Santa Cruz, CA). Peroxidase-conjugated goat-anti-rabbit IgG (Sigma-Aldrich, St. Louis, MO) was used to visualize the sites of primary antibody binding to the antigen. The expression of RAGE was semiquantified by determining the percentage of positive area in a blinded manner using the microscopic planimetry software described above. The inflammatory response after injury was assessed by immunostaining CD45, a specific marker for leukocytes. CD45-positive cells were immunolocalized by incubation with a mouse monoclonal antibody against CD45 (Chemicon International, Temecula, CA) followed by application of a biotinylated rabbit anti-mouse secondary antibody. Detection of CD45 was completed with diaminobenzidine chromogen substrate that produces a brown cells surface stain on CD45-positive cells. Similar semiquantitative analysis was performed.
RAGE mRNA Expression in Vitro and in Vivo. For in vitro study, VSMCs were incubated with incremental concentration of rosiglitazone as described above and 15-deoxy-
12,14-prostaglandin J2 (15d-PGJ2; 1 and 10 µM; a non-TZD PPAR activator) for 24 h. Cells were harvested, and RNA was extracted using RNeasy mini kit (QIAGEN, Valencia, CA). For in vivo study, the total RNA from the vessel segments harvested 7 days after injury was extracted using RNeasy mini kit according to the manufacturer's protocol (QIAGEN) and was then treated with RNase-free RNase for 30 to 60 min (PerkinElmer Life and Analytical Sciences, Boston, MA). Target RNA (1–2 µg) was reverse-transcribed using TaqMan Reverse Transcription Reagent (PerkinElmer Life and Analytical Sciences). The following primer specific for rat RAGE was used: sense (5'-CAACCCAGACTCGAGGAGAG-3') and antisense (5'-AGAAAGTGGCTCGAGGTTGA-3'). Real-time PCR was performed by using the ABI Prism 7700 sequence detector (TaqMan; PerkinElmer Life and Analytical Sciences) to quantify respective tissue mRNA levels. For every reaction set, one RNA sample was performed without reverse transcription to provide a negative control in subsequent PCR reaction. Commercial reagents (TaqMan PCR Reagent kit; PerkinElmer Life and Analytical Sciences) and conditions according to the manufacturer's protocol were applied (2.5 µl of cDNA and oligonucleotides at a final concentration of 200 nM). Each PCR amplification was performed in quadruplicate wells. For all data shown, each individual experiment represented in the n value was performed. In a separate study, to determine whether the effect of rosiglitazone on RAGE is NO-dependent, VSMCs were first pretreated with either 2 mM L-NAME or 1 mM L-arginine for 30 min and then incubated with incremental concentration of rosiglitazone as described above for 24 h. Real-time PCR was performed to determine RAGE expression.
DNA Synthesis. For the animals sacrificed 4 days after injury, the effect of rosiglitazone on VSMC proliferation was evaluated. The rats received intraperitoneal injection of 50 mg/kg bromodeoxyuridine (BrdU) (Sigma-Aldrich) at 18, 12, and 2 h before euthanasia. The assessment of DNA synthesis in vivo was performed using BrdU In Situ Detection kit (BD Biosciences, San Jose, CA). The numbers of BrdU-positive nuclei per section were counted by two observers blinded to the treatment regimens, and the labeling index (positive nuclei/total nuclei) was calculated.
Serum Insulin, Lipids, and Glucose Level Assay. Blood samples were collected before administration of rosiglitazone and at 21 days after injury when animals sacrificed. Serum cholesterol, HDL cholesterol, and LDL cholesterol were determined by the cholesterol oxidase enzyme assay, and triglycerides were determined by the glycerol triphosphate oxidase enzyme assay. Serum glucose level was measured by enzymatic method. Serum insulin level was determined as recommended by manufacturer using enzyme-linked immunosorbent assay kit (Crystal Chem Inc., Downer's Grove, IL).
Statistical Analysis. All data were expressed as mean ± S.D. Statistical analysis was performed with use of SPSS software (SPSS Inc., Chicago, IL). When only two groups were compared, unpaired t tests were applied. When comparing the percentage of reduction of neointimal formation between diabetic and nondiabetic rat cohort, two-way analysis of variance with interaction was performed. A value of P 
0.05 is considered to be statistically significant.
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Results |
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Effects of Rosiglitazone on Neointimal Formation. In total, 60 animals were used in the final data analysis (diabetic rat cohort: 12 rats from the rosiglitazone group, 12 rats from the placebo group, six rats from the sRAGE alone group, and seven from the rosiglitazone plus sRAGE group; nondiabetic rat cohort: 11 rats from the rosiglitazone group and 12 rats from the placebo group). Representative sections from control, rosiglitazone-, and sRAGE-treated nondiabetic and diabetic animals are shown in Fig. 2. The neointimal area in the rosiglitazone-treated groups, either in diabetic or nondiabetic rats, was significantly less at 21 days after injury, compared with that observed in placebo groups (Table 1). In concert with a decrease in neointimal hyperplasia, greater luminal area in the rosiglitazone-treated groups was found. Notably, a greater reduction of neointimal formation was observed in diabetic rats compared with nondiabetic rats (percentage of reduction, 47.6% from diabetic rats versus 20.0% from nondiabetic rats; P < 0.05). Furthermore, the combination treatment of PPAR activation and RAGE inhibition did not display additional, synergistic inhibitory effect on neointimal formation compared with either sRAGE or rosiglitazone treatment alone.
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Immunohistochemical Assay of RAGE Expression and Inflammatory Marker CD45. In total, 16 animals were used in the final data analysis (diabetic rat cohort: four rats from the rosiglitazone group and four rats from the placebo group; nondiabetic rat cohort: four rats from the rosiglitazone group and four rats from the placebo group). Immunohistochemical analysis showed that compared with the control group, rosiglitazone treatment significantly reduced the RAGE expression by 66% in diabetic rats and by 69% in nondiabetic rats, as assessed by percentage of positive area for RAGE-positive cells (diabetic rats: 6.22 ± 3.25 versus 18.54 ± 4.62%; P = 0.005; nondiabetic rats: 4.59 ± 1.55 versus 15.09 ± 2.20%; P < 0.001; Fig. 3). The treatment with rosiglitazone also significantly decreased the inflammatory response after injury as evidenced by CD45 staining, with a greater extent in diabetic rats. In diabetic rats, a 51% relative reduction was observed with rosiglitazone treatment (9.26 ± 2.37 versus 18.99 ± 4.00%; P = 0.006), and a 37% reduction was seen in nondiabetic rats (9.09 ± 2.05 versus 14.46 ± 2.24%; P = 0.012).
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Real-Time PCR for RAGE mRNA Expression. For the in vivo study, 12 animals in total were used in the final data analysis (diabetic rats cohort: three rats from the rosiglitazone group and three rats from the placebo group; nondiabetic rats cohort: three rats from the rosiglitazone group and three rats from the placebo group). Real-time PCR showed that RAGE expression was up-regulated after injury in diabetic and nondiabetic rats. The treatment with rosiglitazone significantly reduced RAGE mRNA expression in both diabetic and nondiabetic rats (Fig. 4). For the in vitro study, RAGE mRNA level was much higher in the control group and was significantly decreased by both rosiglitazone and 15d-PGJ2 treatment, a non-TZD PPAR activator (Fig. 5). Furthermore, the effect of rosiglitazone on RAGE expression was found to be NO-dependent; L-NAME, an inhibitor of NO synthesis, blocked the inhibitory effect of rosiglitazone on RAGE expression, whereas a synergistic inhibitory effect on RAGE expression was found in the group treated with both rosiglitazone and L-arginine (Fig. 6).
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Effect of Rosiglitazone on DNA Synthesis. The number of BrdU-labeled positive cells in the intima and media was greatly diminished by rosiglitazone (25.0 ± 4 versus 63.0 ± 17 cells per cross-section; P = 0.02), as was the BrdU labeling index (7 ± 2 versus 18 ± 3%; P = 0.006) (Fig. 7), indicating rosiglitazone significantly suppressed the VSMC proliferation compared with vehicle treatment.
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Serum Insulin, Lipids, and Glucose Level Assay. The serum total cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride levels as well as fasting glucose levels before and after rosiglitazone treatment were depicted in Table 2. There were no differences in serum LDL and very LDL levels or blood glucose levels before and after rosiglitazone treatment. There was a trend toward decreased triglycerides [diabetic rats: 371.2 ± 72.4 mg/dl (before treatment) versus 309.8 ± 71.6 mg/dl (after treatment); P = 0.073; nondiabetic rats: 63.3 ± 34.4 mg/dl (before treatment) versus 39.7 ± 15.7 mg/dl (after treatment); P = 0.080] and cholesterol levels [diabetic rats: 232.8 ± 15.1 mg/dl (before treatment) versus 212.3 ± 27.6 mg/dl (after treatment); P = 0.054; nondiabetic rats: 92.8 ± 10.2 mg/dl (before treatment) versus 82.9 ± 11.8 mg/dl (after treatment); P = 0.075]. However, rosiglitazone treatment significantly decreased HDL levels in both diabetic and nondiabetic rats. This finding is in consistent with the finding by previous study (Li et al., 2000), in which a decrease in HDL cholesterol levels was observed in the mice treated with rosiglitazone, although it is in contrast to other findings (Fonseca et al., 2000; Lebovitz et al., 2001), which showed that rosiglitazone increased HDL cholesterol and reduced triglycerides.
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Insulin levels in diabetic rats were significantly decreased by 42% with rosiglitazone treatment. There was no difference found in insulin level in nondiabetic rats before and after rosiglitazone treatment.
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Discussion |
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significantly decreases neointimal formation after vascular injury in the rat carotid injury model. This reduction was greater in the diabetic rats compared with nondiabetic rats. The findings of this study highlight this receptor's potential role in the prevention of restenosis, especially in the diabetic patients.
PPAR is expressed in all vascular cells, including VSMCs, endothelial cells, and monocytes/macrophages. It has been shown that its ligands such as TZDs inhibit VSMC proliferation and migration (Law et al., 1996; Marx et al., 1998a,b; Li et al., 2000; Wakino et al., 2000), which are important to the process of neointimal formation after injury. Their antiproliferative effects are believed to be via cell cycle arrest in the G1. In VSMCs, proliferation and apoptosis may be competing processes during the formation of restenotic lesions. Aizawa et al. (2001) showed that pioglitazone, one member of TZDs and a PPAR ligand, enhanced cytokine-induced apoptosis, an important mechanism of formation of vascular lesions, in VSMCs and decreased the neointimal hyperplasia. This finding was confirmed by Bruemmer et al. (2003), who found that the TZDs induce caspasemediated apoptosis of human coronary VSMCs. Induction of VSMC apoptosis correlated closely with an up-regulation of growth arrest and DNA damage-inducible gene 45 (GADD45) mRNA expression and transcription, a well recognized modulator of cell cycle arrest and apoptosis.
In the past decade, the role of inflammation in the repair process after vascular injury has been increasingly appreciated. PPAR is expressed in human and rodent monocyte/macrophages (Marx et al., 1998a,b; Ricote et al., 1998a,b; Law et al., 2000) and has been shown to have several potential anti-inflammatory effects that could modulate neointimal hyperplasia, including macrophage activation and cytokines production (Jiang et al., 1998; Ricote et al., 1998a,b), down-regulation of endothelial cell vascular cell adhesion molecule expression, inhibition of monocyte migration (Marx et al., 1998a; Jackson et al., 1999; Kinstcher et al., 2000), and down-regulation of CCR2 (Han et al., 2000), the receptor for monocyte chemoattractant protein-1, which is involved in the process of neointimal hyperplasia after vascular injury (Furukawa et al., 1999; Mori et al., 2002). Our study demonstrates that PPAR activation leads to a decrease in the expression of CD45, a specific marker for leukocytes, and inhibits neointimal formation.
An important finding from the current study is the demonstration for the first time in vivo that activation of PPAR down-regulates the expression of RAGE, a multiligand member of the immunoglobulin superfamily. Our finding is consistent with the previous in vitro study, in which it has been shown that TZDs decreased human endothelial cell RAGE mRNA expression (Marx et al., 2004). It has been shown that RAGE and its ligands, AGEs and S100/calgranulins, are highly up-regulated at the sites of vascular injury (Park et al., 1998; Bucciarelli et al., 2002; Wendt et al., 2002; Sakaguchi et al., 2003), and we have previously demonstrated that blocking RAGE activation following arterial injury leads to a decrease in neointimal formation. Ligand-triggered RAGE-dependent cellular activation augments inflammatory responses after vascular injury and enhances cellular migration and proliferation (Schmidt et al., 1993, 1994; Hofmann et al., 1999). In addition, binding of RAGE to its ligand leads to activation of key cell signaling pathways, such as p44/p42 (extracellular signal-regulated kinase 1/extracellular signalregulated kinase 2), p21ras, mitogen-activated protein kinases, nuclear factor-
B, cdc42/rac, and Janus tyrosine kinase/signal transducer and activator of transcription, thereby reprogramming cellular properties (Lander et al., 1997; Huttunen et al., 1999). Furthermore, blockade of advanced glycosylation end product/RAGE interaction decreases mitogen-activated protein kinase activity in cultured VSMCs and neointimal formation in vivo (Lander et al., 1997; Park et al., 1998; Zhou et al., 2003).
To determine whether PPAR works through RAGE and/or through another anti-inflammatory pathway, we studied the combined effects of PPAR and sRAGE. We hypothesized that if the effects of PPAR was through RAGE alone, then the combination of PPAR agonist and sRAGE would not have additional effects compared with either alone. sRAGE functionally works as a sink for RAGE agonists and thus does not bind to cells. Therefore, the administration of sRAGE would not block the ability of PPAR to inhibit neointimal hyperplasia by a non-RAGE mechanism. We did not observe an additive effect of sRAGE and PPAR. The lack of an additive effect suggests and is consistent with our hypothesis that PPAR mediates its effects on neointimal hyperplasia through the down-regulation of RAGE. However, the mechanism of down-regulation of RAGE expression by PPAR is not investigated. Previous studies have shown that PPAR activation suppresses induction of Egr-1 and its inflammatory gene target (Okada et al., 2002; Cheng et al., 2004). It is unreasonable to speculate that down-regulation of RAGE expression by PPAR is mediated by inhibition of the Egr-1 signaling pathway. Although it has also been reported that PPAR ligands enhance cytokine-induced apoptosis in an NO-dependent manner (Aizawa et al., 2001), and our initial data showed that NO production was required for the downregulation of RAGE by PPAR activation. The further study on these pathways or others will elucidate the mechanism of down-regulation of RAGE expression by PPAR and provide a direct link between PPAR and treatment strategies for restenosis and atherosclerosis, because RAGE directly influences vascular cell proliferation and inflammation, a key event in development of atherosclerotic and restenotic lesions, especially in the diabetic setting.
The present study implicates PPAR as a target for limiting the development and progression of neointimal hyperplasia after vascular injury. Our data suggest a crucial role of PPAR in regulating VSMCs proliferation and migration through the down-regulation of RAGE expression and inflammatory response. Activation of PPAR resulted in 47% reduction of neointimal formation in diabetic rats and 20% in nondiabetic rats. Specifically, the present study has important implications for diabetic patients. In type 2 diabetes, the development of both atherosclerosis and restenosis is substantially accelerated. TZDs, therefore, may provide a dual benefit for type 2 diabetes by ameliorating insulin resistance and its metabolic sequelae, including the generation of AGEs, as well as through the down-regulation of the inflammatory response following arterial injury via the down-regulation of RAGE.
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Footnotes |
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ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor ; SMC, smooth muscle cell; VSMC, vascular smooth muscle cell; TZD, thiazolidinedione; RAGE, advanced glycosylation end product(s); sRAGE, soluble advanced glycosylation end product(s); PCR, polymerase chain reaction; 15d-PGJ2, 15-deoxy-12,14-prostaglandin J2; L-NAME, N
-nitro-L-arginine methyl ester; BrdU, bromodeoxyuridine; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
Address correspondence to: Dr. Kai Wang, Department of Cardiovascular Medicine F25, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. E-mail: wangk{at}ccf.org
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