Published online before print February 14, 2008, doi: 10.1161/ATVBAHA.108.162305
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© 2008 American Heart Association, Inc.
Clinical and Population Studies |
A Potential Role of the CXC Chemokine GRO
in Atherosclerosis and Plaque Destabilization
Downregulatory Effects of Statins
From the Research Institute for Internal Medicine (U.M.B., B.H., A.Y., C.S., K.O., T.W., W.J.S., S.S.F., J.K.D., P.A.), the Department of Pathology (J.H., G.H.), the Department of Cardiology (E.Ø., L.G.), the Institute for Surgical Research (E.Ø.), and the Section of Clinical Immunology and Infectious Diseases (S.S.F., J.K.D., P.A.), Rikshospitalet, University of Oslo, Norway; and the Department of Surgery (U.H.) and the Department of Medicine and Centre for Molecular Medicine (G.P.-B., G.K.H.), Karolinska University Hospital, Stockholm, Sweden.
Correspondence to Unni M. Breland, Research Institute for Internal Medicine, Rikshospitalet, N-0027 Oslo, Norway. E-mail Unni.Mathilde. Breland{at}rr-research.no
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Abstract |
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Objective— We examined the role of the CXCR2 ligand growth-related oncogene (GRO)
in human atherosclerosis.
Methods and Results— GRO levels were examined by enzyme immunoassay, real-time quantitative RT-PCR, and cDNA microarrays. The in vitro effect of statins on GRO was examined in endothelial cells and THP-1 macrophages. Our main findings were: (1) GRO was among the 10 most differentially expressed transcripts comparing peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD) and healthy controls. (2) Both patients with stable (n=41) and particularly those with unstable (n=47) angina had increased plasma levels of GRO comparing controls (n=20). (3) We found increased expression of GRO within symptomatic carotid plaques, located to macrophages and endothelial cells. (4) GRO enhanced the release of matrix metalloproteinases in vascular smooth muscle cells, and increased the binding of acetylated LDL in macrophages. (5) Atorvastatin downregulated GRO levels as shown both in vitro in endothelial cells and macrophages and in vivo in PBMCs from CAD patients. (6) The effect on GRO in endothelial cells involved increased storage and reduced secretion of GRO.
Conclusions— GRO could be involved in atherogenesis and plaque destabilization, potentially contributing to inflammation, matrix degradation, and lipid accumulation within the atherosclerotic lesion.
The involvement of CXCR2 in atherogenesis is well recognized, thought to reflect interaction with interleukin-8. In the present study we found another CXCR2 ligand (ie, GRO) to be significantly upregulated in human atherosclerosis both in circulating leukocytes and within the atherosclerotic lesion, potentially promoting matrix degradation, lipid accumulation, and inflammation.
Key Words: atherosclerosis • chemokines • inflammation • endothelium
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Coronary artery disease (CAD) is a chronic progressive disorder where the pathogenesis is multifactorial and involves lipid deposition, thrombus formation, matrix degradation, and inflammation. In all steps of this process, regulation by inflammatory cytokines seems to play a central role, but there are still issues to be clarified, and the precise mechanisms of action of each of the inflammatory participants have not been elucidated.1
Chemokines are thought to be important actors in the inflammatory process characterizing atherogenesis and plaque destabilization. Thus, increased expression of IL-82 and monocyte chemoattractant protein (MCP)-13 has been found within atherosclerotic plaques in humans, and targeted disruption of the genes for MCP-1,4 CCR2 (ie, MCP-1 receptor),5 and CXCR2,6 which binds IL-8, significantly decreases atherosclerotic lesion formation in mice prone to developing atherosclerosis. CXCR2 is 1 of 2 functional IL-8 receptors that also bind other CXC chemokines like growth-related oncogene (GRO). As no murine IL-8 homologue has been described,7 but disruption of CXCR2 ameliorates murine atherosclerosis, we believe that other CXCR2 ligands are of importance in this process. This hypothesis is strengthened by the observation that GRO rather than MCP-1 promotes monocyte arrest in inflamed endothelium in apolipoprotein E–/– mice.8 However, although there are several reports on IL-8 in human CAD, few studies have examined the role of other CXCR2 ligands in human atherosclerosis.
In the present study, we identified GRO as a potentially important mediator of atherogenesis by using DNA microarrays to identify transcripts for cytokines in peripheral blood mononuclear cells (PBMCs) that were differently expressed in CAD patients and healthy controls. We further examined the possible role of this CXC chemokine in atherosclerosis by several approaches including clinical studies in CAD patients and experimental studies in cells with relevance to atherogenesis. We also examined the ability of statins to modulate the expression of GRO in vitro and in vivo.
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Materials and Methods |
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Patients and Controls
In the initial screening experiments with DNA microarrays and subsequent real-time RT-PCR analyses, we used PBMCs from 13 CAD patients with previous myocardial infarction (MI). In a subsequent study we analyzed plasma samples from consecutively recruited angina patients undergoing clinically indicated coronary angiography (supplemental Table I, available online at http://atvb. ahajournals.org). A detailed description of the patient population and procedures for blood collection is given in the Data Supplemental file (available online at http://atvb.ahajournals.org).
Measurement of Matrix Metalloproteinases
Matrix metalloproteinase (MMP) levels in vascular SMC supernatants were measured by multiplex suspension array technology using the BioPlex (Bio-Rad). MMP-1, MMP-2, and MMP-3 multiplexable beads were purchased from R&D Systems.
Enzyme Immunoassay
Levels of GRO were measured in duplicates by enzyme immunoassay (R&D Systems).
A detailed description of cell isolation, cell culture experiments, tissue sampling from carotid plaques, immunocytofluorescent staining and confocal microscopy, binding of Alexa-labeled acetylated low-density lipoprotein (acLDL), cDNA microarrays, real-time quantitative RT-PCR, immunohistochemistry, and statistical analyzes is given in the Data Supplemental file.
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Results |
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GRO
Expression in CADTo screen for genes that were regulated differently in CAD patients and healthy controls, we used oligonucleotide microarrays encoding 8500 human genes to analyze the gene expression profiles in PBMCs isolated from 4 healthy controls and 6 randomly selected patients from the CAD population. When analyzing cytokines or growth factors, GRO
was among the 10 most differentially expressed transcripts. The increased expression of GRO in CAD patients was confirmed by real-time RT-PCR when analyzing PBMCs from 13 CAD patients and 9 healthy controls (Figure 1A). Several studies support a role of CXCR2 in atherogenesis,9 and interestingly, in the initial screening experiment by microarrays, also transcripts of the 2 other GRO-related chemokines (ie, GRO
, P=0.004 and GROβ, P=0.05) and IL-8 (P=0.05) was upregulated in PBMCs from CAD patients, underscoring the potential importance of GRO-related chemokines in human CAD. As for the other CXCR2 ligands (ie, neutrophil-activating peptide-2, epithelial neutrophil-activating peptide-78, granulocyte chemotactic protein-2, and migration inhibitory factor [MIF]), there were no significant increase in CAD patients as compared with controls.
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GRO Levels in Stable and Unstable Angina Patients
To examine GRO levels in relation to plaque instability, we next analyzed plasma levels of GRO in stable and unstable angina patients by means of enzyme immunoassay. Both patients with stable (n=41) and unstable (n=47) angina had increased plasma levels of GRO compared to healthy controls (n=20), with particularly high levels in those with unstable disease (Figure 1B). Some of the patients had additional risk factors that could interfere with inflammatory responses (eg, diabetes and hypertension; supplemental Table I), but the same pattern of GRO levels was observed even if these patients were excluded from the study. Moreover, although there were a higher proportion of women in the unstable angina group (supplemental Table I), we found the same pattern of GRO levels in both genders.
To further examine the systemic expression of GRO in angina patients, we analyzed mRNA levels of GRO in T cells and monocytes from 14 of the patients with unstable angina, 14 of the patients with stable angina, and in 10 of the controls. As shown in supplemental Figure IA, monocytes from angina patients had increased mRNA levels of GRO as compared with controls, reaching statistical significance in those with unstable disease. In contrast, T cells from unstable angina patients tended to express lower GRO mRNA levels than T cells from healthy controls and stable angina patients (supplemental Figure IB).
Expression of GRO in Human Atherosclerotic Lesions
To characterize GRO expression within the atherosclerotic lesion, we analyzed the mRNA levels of GRO in atherosclerotic tissue, collected from patients undergoing carotid endarterectomy (n=47), and in control tissue, obtained from iliac arteries of organ donors (n=10), by means of Affymetrix Gene Array analysis (Biobank of Karolinska Endarterectomies study).10 As depicted in supplemental Figure II, carotid plaques showed significantly elevated mRNA levels of GRO as compared with control samples from nonatherosclerotic arteries (
2.5 fold increase). Moreover, the expression of GRO within the atherosclerotic plauqes was significantly correlated with mRNA levels of CD68 (r=0.29, P=0.04), suggesting that macrophages contribute to the increased expression of GRO within these lesions. In line with this, when examining GRO expression within the carotid lesions (n=4) by means of immuhistochemistry, we found immunostaining for GRO located in lipid-rich areas with strong immunostaining against calprotectin-positive macrophages and within von Willebrand-positive endothelial cells (Figure 2). In nonatherosclerotic renal arteries (n=2) GRO immunoreactivity was only seen within the endothelium (data not shown).
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The effect of GRO on MMP Release in Vascular SMCs
Our findings so far suggest increased expression of GRO in atherosclerotic disorders both systemically and within the plaque, with particularly high levels in those with unstable disease. We have previously reported increased expression of CXCR1 and CXCR2 (ie, the GRO receptors) in SMCs and macrophages within human atherosclerotic lesions.11 To map any potential pathogenic consequences of the raised GRO levels in atherosclerotic disorders, we therefore first examined the effect of GRO on the release of MMP in vascular SMCs. Although GRO had no effect on its own, it boosted the release of MMP-1 and MMP-3, induced by low levels of IL-1β (0.1 ng/mL, supplemental Figure III), an inflammatory cytokine that is increased in CAD.12 This enhancing effect was attenuated by adding anti-CXCR2 and anti-CXCR1, but not by control antibodies, suggesting that this GRO-mediated effect may involve both CXCR1 and CXCR2 (supplemental Figure III).
GRO Enhances Lipid Accumulation in THP-1 Macrophages
We next examined the ability of GRO to modulate the interaction between macrophages and lipids. As depicted in Figure 3A and 3B, GRO markedly increased the binding of fluorescence-labeled acLDL in THP-1 macrophages, suggesting that this chemokine could promote foam cell formation. AcLDL binds preferentially to SR-A,13 and interestingly, GRO enhanced the mRNA levels of the scavenger receptors SR-A and CD36, but not the expression of LOX-1, in THP-1 macrophages (Figure 3C). The combined increase in SR-A and CD36 expression in GRO-activated macrophages further support a role for GRO in lipid accumulation and foam cell formation. Finally, the enhancing effect of GRO on acLDL binding was nearly abolished by adding anti-CXCR2, with a moderate and not significant effect of anti-CXCR1 antibodies (Figure 3D).
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Effects of Statins on GRO in Endothelial Cells
Experimental and some clinical data indicate that statins may confer some of their cardiovascular benefits by modulating the inflammatory arm of atherosclerosis.14 We therefore next examined the ability of the atorvastatin metabolite ortho-hydroxy atorvastatin to modulate the levels of GRO in endothelial cells and macrophages, both cell types showing strong GRO immunoreactivity within the atherosclerotic carotid plaques. To mimic the in vivo situation in atherosclerosis, the cells were stimulated for 20 hours with IL-1β (5 ng/mL). Ortho-hydroxy atorvastatin induced a modest, but significant decrease in GRO release from IL-1β–activated HUVECs, and this inhibition was attenuated by the addition of mevalonate, suggesting that this effect of statin may be operative at the cellular level (supplemental Figure IVA). In contrast, ortho-hydroxy atorvastatin had no effect on gene expression of GRO in resting or IL-1–activated HUVECs, suggesting that ortho-hydroxy atorvastatin inhibits GRO release from endothelial cells at the post-transcriptional level (supplemental Figure IVB). This observation combined with our recent demonstration that GRO can be stored in small secretagogue-responsive cytoplasmic granules15 led us to perform paired immunostaining and confocal analysis, showing that ortho-hydroxy atorvastatin in a dose-dependent manner significantly increased GRO staining in IL-1β-activated HUVECs (Figure 4). Signal was detected in the Golgi apparatus and in cytoplasmic granula that with ortho-hydroxy atorvastatin treatment became larger and more numerous (Figure 4). These findings suggest that ortho-hydroxy atorvastatin inhibits exocytosis of IL-1β–induced GRO, but not the transcription of this chemokine.
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Effects of Statins on the Release of GRO in Macrophages
The release of GRO was markedly increased during differentiation of THP-1 cells from monocytes to macrophages (data not shown), and ortho-hydroxy atorvastatin significantly reduced the IL-1β–induced (10 ng/mL) secretion of GRO in THP-1 macrophages after culturing for 24 hours (Figure 5A). However, in contrast to HUVECs, this downregulatory effect of ortho-hydroxy atorvastatin was also seen at mRNA level, and this effect was reversed by mevalonate (Figure 5B).
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The In Vivo Effects of Statins on GRO Expression in PBMCs
To examine the in vivo relevance of the statin-mediated effects on GRO in vitro, we analyzed the mRNA levels of GRO by real time RT-PCR in PBMCs before and after 6 months of atorvastatin therapy (80 mg qd). We have previously reported the effect of low-dose simvastatin and high-dose atorvastatin on inflammatory markers in CAD patients without previous statin treatment,16 and from this study, PBMCs were available from 8 patients (age 60.3±3.1 years, 1 woman and 7 men) randomly assigned to atorvastatin treatment. The decrease in lipid parameters during statin therapy (data not shown) was accompanied by a significant decrease in gene expression of GRO in PBMCs (Figure 6A). However, there was no significant correlation between the decrease in LDL cholesterol and the decrease in GRO expression during statin therapy (Figure 6B), suggesting that the decrease in GRO may not be secondary to lipid lowering. Finally, based on Affymetrix gene array data from PBMCs in 6 CAD patients before and 6 months after initiating therapy, we found a downregulatory effect of atorvastatin not only on GRO, but also on the 2 other members of the GRO family (ie, GROβ and GRO, P<0.03 for both), underscoring the ability of atorvastatin to downregulate GRO-related chemokines in CAD.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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High-level expression of CXCR2 by macrophages has been detected in advanced atherosclerotic lesions of patients11 and LDL receptor (LDLR)-deficient mice.6 CXCR2 expression has also been shown to be proatherogenic in that CXCR2 deficiency significantly reduces the progression of advanced atherosclerosis in mice.6 Although most attention has been directed against IL-8 as a CXCR2 ligand in this process, there are also reports of increased GRO
expression in relation to atherogenesis. To this end, inflammatory cytokines (eg, IL-1 and tumor necrosis factor [TNF] ), thrombin, oxidized LDL (oxLDL), and shear stress have all been found to induce GRO expression in endothelial cells.17–21 Shear stress has also been reported to induce GRO expression in murine atherosclerosis,22 and we have previously reported raised plasma levels of GRO in angina patients.23 Herein, we extend these findings by identifying GRO as one of the most strongly induced cytokines in PBMCs from CAD patients when compared to healthy individuals. Upregulation of GRO was also related to plaque instability as shown by particularly elevated GRO expression in unstable angina, as demonstrated both at the protein (plasma) and mRNA (monocytes) level. The relevance of our findings to human atherosclerosis was further supported by observing increased expression of GRO within symptomatic carotid plaques, primarily located to macrophages and endothelial cells. These data indicate that GRO should be added to the list of CXCR2 ligands that could be involved in atherogenesis and plaque destabilization in man.
In the present study we found increased expression of GRO-related chemokines (ie, GRO, GROβ, and GRO) and IL-8, but not of the other CXCR2 ligands, in PBMCs from CAD patients. This, however, does not exclude an important role for other CXCR2 ligands in atherogenesis. Hence, deficiency in leukocyte CXCR2 was recently reported to have more profound effects on atherogenesis in LDLR–/– mice than deficiency in GRO, supporting the importance of additional CXCR2 ligands.24 Moreover, MIF, a recently described functional noncognate ligand for CXCR2,25 has been shown to be crucial for plaque progression and an unstable plaque phenotype.25,26 However, these data are based on in vitro experiments and studies in animal models, and the relative importance of the various CXCR2 ligands in atherogenesis and plaque destabilization in human will have to be further elucidated.
Previous studies have shown that GRO can support monocyte arrest to endothelium in models of inflammation.19 The relevance of this to atherosclerosis was recently shown by Boisvert et al demonstrating that deficiency of murine GRO was associated with a loss of intimal macrophages and attenuated disease progression in LDLR–/– mice.24 In the present study, we show that the proatherogenic effects of GRO may not be limited to chemotactic and firm adhesion-activating properties. We found that this CXC chemokine also has the ability to enhance IL-1–driven MMP secretion in vascular SMCs, potentially transforming these cells into a secretory phenotype thought to affect the vulnerability of the plaque. Although GRO had no MMP-inducing effect alone, it is reasonable to assume that within an atherosclerotic plaque, GRO interacts with other inflammatory mediators that most likely include low levels of IL-1β.12 Moreover, whereas GRO has been reported to promote macrophage accumulation within atherosclerotic lesions in murine models,24 we show that GRO also enhanced the binding of acLDL to THP-1 macrophages in a CXCR2-dependent manner, potentially promoting foam cell formation. Thus, although oxLDL has been shown to induce GRO expression in endothelial cells24 and PBMCs,27 our present findings indicate that GRO in turn may enhance the accumulation of modified LDL in macrophages. If such mechanisms operate in vivo within an atherosclerotic lesion, they could be part of a pathogenic loop, representing a molecular link between inflammation, lipid accumulation, and matrix degradation during atherogenesis.
Several reports suggest that statins may confer cardiovascular benefits in addition to their lipid lowering activity, at least partly by modulating the inflammatory arm of atherosclerosis.14,28 In the present study, we demonstrated downregulatory effects of atorvastatin on GRO levels as shown both in vitro in endothelial cells and macrophages and in vivo in PBMCs from CAD patients. However, the mechanism by which atorvastatin inhibits GRO release seems to differ between endothelial cells and macrophages. Thus, whereas the atorvastatin-mediated downregulation of GRO in macrophages was seen both at the protein and mRNA levels, the effect on GRO release in endothelial cells appears to operate at the posttranscriptional level and involves increased storage and reduced secretion of GRO. Lipophilic statins have previously been reported to suppress NK cell activity through inhibition of the exocytosis pathway,29 and Yamakuchi et al30 reported that simvastatin suppresses exocytosis of Weibel-Palade bodies by endothelial cells. We have recently showed that GRO is stored in endothelial cells and released from an intracellular compartment distinct from the IL-8/eotaxin-3-containing Weibel-Palade bodies,15 and our findings suggest that statins may enhance sorting of these granules but inhibit secretion. Inhibition of endothelial cell exocytosis could represent a novel mechanism by which statins reduce vascular inflammation involving decreased release of chemokines such as GRO.
Several lines of evidence support a pathogenic role of chemokines in atherogenesis and plaque destabilization.31 Our present findings suggest that the CXC chemokine GRO could be an important mediator in these processes, potentially contributing to inflammation, matrix degradation, and lipid accumulation within the atherosclerotic lesion. The gradual increase in GRO levels in relation to plaque instability, potentially at least partly reflecting increased release from the plaque, suggest that forthcoming studies should explore the potential role of GRO as a prognostic marker in atherosclerosis. Our demonstration of increased GRO expression both in the circulation and within the atherosclerotic lesion in patients with atherosclerotic disorders also underscores that the proatherogenic effects of GRO are operational in vivo, potentially representing a novel therapeutic target in atherosclerosis.
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Acknowledgments |
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The authors thank Ellen Lund Sagen and Morten Mattingsdal (Joint Centre for Bioinformatics, Oslo) for excellent technical assistance.
Sources of Funding
This work was supported by grants from the Norwegian Council of Cardiovascular Research, Research Council of Norway, University of Oslo, Medinnova Foundation, Helse Sør, Rikshospitalet, Swedish Medical Research Council, and Swedish Heart-Lung Foundation.
Disclosures
None.
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Footnotes |
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B.H. and J.H. contributed equally to this study.
Original received October 24, 2007; final version accepted January 29, 2008.
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References |
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1. Packard RR, Libby P. Inflammation in Atherosclerosis: From Vascular Biology to Biomarker Discovery and Risk Prediction. Clin Chem. 2008; 54: 24–38.
2. Satterthwaite G, Francis SE, Suvarna K, Blakemore S, Ward C, Wallace D, Braddock M, Crossman D. Differential gene expression in coronary arteries from patients presenting with ischemic heart disease: further evidence for the inflammatory basis of atherosclerosis. Am Heart J. 2005; 150: 488–499.[CrossRef][Medline] [Order article via Infotrieve]
3. Nelken NA, Coughlin SR, Gordon D, Wilcox JN. Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest. 1991; 88: 1121–1127.[Medline] [Order article via Infotrieve]
4. Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell. 1998; 2: 275–281.[CrossRef][Medline] [Order article via Infotrieve]
5. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998; 394: 894–897.[CrossRef][Medline] [Order article via Infotrieve]
6. Boisvert WA, Santiago R, Curtiss LK, Terkeltaub RA. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J Clin Invest. 1998; 101: 353–363.[Medline] [Order article via Infotrieve]
7. Fan X, Patera AC, Pong-Kennedy A, Deno G, Gonsiorek W, Manfra DJ, Vassileva G, Zeng M, Jackson C, Sullivan L, Sharif-Rodriguez W, Opdenakker G, Van DJ, Hedrick JA, Lundell D, Lira SA, Hipkin RW. Murine CXCR1 is a functional receptor for GCP-2/CXCL6 and interleukin-8/CXCL8. J Biol Chem. 2007; 282: 11658–11666.
8. Huo Y, Weber C, Forlow SB, Sperandio M, Thatte J, Mack M, Jung S, Littman DR, Ley K. The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium. J Clin Invest. 2001; 108: 1307–1314.[CrossRef][Medline] [Order article via Infotrieve]
9. Boisvert WA, Curtiss LK, Terkeltaub RA. Interleukin-8 and its receptor CXCR2 in atherosclerosis. Immunol Res. 2000; 21: 129–137.[CrossRef][Medline] [Order article via Infotrieve]
10. Qiu H, Gabrielsen A, Agardh HE, Wan M, Wetterholm A, Wong CH, Hedin U, Swedenborg J, Hansson GK, Samuelsson B, Paulsson-Berne G, Haeggstrom JZ. Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc Natl Acad Sci U S A. 2006; 103: 8161–8166.
11. Smith C, Damas JK, Otterdal K, Oie E, Sandberg WJ, Yndestad A, Waehre T, Scholz H, Endresen K, Olofsson PS, Halvorsen B, Gullestad L, Froland SS, Hansson GK, Aukrust P. Increased levels of neutrophil-activating peptide-2 in acute coronary syndromes: possible role of platelet-mediated vascular inflammation. J Am Coll Cardiol. 2006; 48: 1591–1599.
12. Waehre T, Yndestad A, Smith C, Haug T, Tunheim SH, Gullestad L, Froland SS, Semb AG, Aukrust P, Damas JK. Increased expression of interleukin-1 in coronary artery disease with downregulatory effects of HMG-CoA reductase inhibitors. Circulation. 2004; 109: 1966–1972.
13. Suzuki H, Kurihara Y, Takeya M, Kamada N, Kataoka M, Jishage K, Ueda O, Sakaguchi H, Higashi T, Suzuki T, Takashima Y, Kawabe Y, Cynshi O, Wada Y, Honda M, Kurihara H, Aburatani H, Doi T, Matsumoto A, Azuma S, Noda T, Toyoda Y, Itakura H, Yazaki Y, Kodama T. A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature. 1997; 386: 292–296.[CrossRef][Medline] [Order article via Infotrieve]
14. Schonbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Circulation. 2004; 109: II18–II26.[Medline] [Order article via Infotrieve]
15. Oynebraten I, Barois N, Hagelsteen K, Johansen FE, Bakke O, Haraldsen G. Characterization of a novel chemokine-containing storage granule in endothelial cells: evidence for preferential exocytosis mediated by protein kinase A and diacylglycerol. J Immunol. 2005; 175: 5358–5369.
16. Waehre T, Damas JK, Gullestad L, Holm AM, Pedersen TR, Arnesen KE, Torsvik H, Froland SS, Semb AG, Aukrust P. Hydroxymethylglutaryl coenzyme a reductase inhibitors down-regulate chemokines and chemokine receptors in patients with coronary artery disease. J Am Coll Cardiol. 2003; 41: 1460–1467.
17. Weber KS, von HP, Clark-Lewis I, Weber PC, Weber C. Differential immobilization and hierarchical involvement of chemokines in monocyte arrest and transmigration on inflamed endothelium in shear flow. Eur J Immunol. 1999; 29: 700–712.[CrossRef][Medline] [Order article via Infotrieve]
18. Wen DZ, Rowland A, Derynck R. Expression and secretion of gro/MGSA by stimulated human endothelial cells. EMBO J. 1989; 8: 1761–1766.[Medline] [Order article via Infotrieve]
19. Murakami K, Ueno A, Yamanouchi K, Kondo T. Thrombin induces GRO alpha/MGSA production in human umbilical vein endothelial cells. Thromb Res. 1995; 79: 387–394.[CrossRef][Medline] [Order article via Infotrieve]
20. Hagiwara H, Mitsumata M, Yamane T, Jin X, Yoshida Y. Laminar shear stress-induced GRO mRNA and protein expression in endothelial cells. Circulation. 1998; 98: 2584–2590.
21. Lei Z, Wen C, Xu J, Li X, Qing L, Wei M. OxLDL upregulates growth-regulation oncogene alpha expression in human endothelial cells. Chin Med J. 2001; 114: 1240–1244.[Medline] [Order article via Infotrieve]
22. Cheng C, Tempel D, van HR, de Boer HC, Segers D, Huisman M, van Zonneveld AJ, Leenen PJ, van der SA, Serruys PW, de CR, Krams R. Shear stress-induced changes in atherosclerotic plaque composition are modulated by chemokines. J Clin Invest. 2007; 117: 616–626.[CrossRef][Medline] [Order article via Infotrieve]
23. Aukrust P, Berge RK, Ueland T, Aaser E, Damas JK, Wikeby L, Brunsvig A, Muller F, Forfang K, Froland SS, Gullestad L. Interaction between chemokines and oxidative stress: possible pathogenic role in acute coronary syndromes. J Am Coll Cardiol. 2001; 37: 485–491.
24. Boisvert WA, Rose DM, Johnson KA, Fuentes ME, Lira SA, Curtiss LK, Terkeltaub RA. Up-regulated expression of the CXCR2 Ligand KC/GRO-alpha in atherosclerotic lesions plays a central role in macrophage accumulation and lesion progression. Am J Pathol. 2006; 168: 1385–1395.
25. Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, Kooistra T, Fingerle-Rowson G, Ghezzi P, Kleemann R, McColl SR, Bucala R, Hickey MJ, Weber C. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med. 2007; 13: 587–596.[CrossRef][Medline] [Order article via Infotrieve]
26. Schober A, Bernhagen J, Thiele M, Zeiffer U, Knarren S, Roller M, Bucala R, Weber C. Stabilization of atherosclerotic plaques by blockade of macrophage migration inhibitory factor after vascular injury in apolipoprotein E-deficient mice. Circulation. 2004; 109: 380–385.
27. Holm T, Damas JK, Holven K, Nordoy I, Brosstad FR, Ueland T, Wahre T, Kjekshus J, Froland SS, Eiken HG, Solum NO, Gullestad L, Nenseter M, Aukrust P. CXC-chemokines in coronary artery disease: possible pathogenic role of interactions between oxidized low-density lipoprotein, platelets and peripheral blood mononuclear cells. J Thromb Haemost. 2003; 1: 257–262.[CrossRef][Medline] [Order article via Infotrieve]
28. Liao JK. Effects of statins on 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition beyond low-density lipoprotein cholesterol. Am J Cardiol. 2005; 96: 24F–33F.[Medline] [Order article via Infotrieve]
29. Tanaka T, Porter CM, Horvath-Arcidiacono JA, Bloom ET. Lipophilic statins suppress cytotoxicity by freshly isolated natural killer cells through modulation of granule exocytosis. Int Immunol. 2007; 19: 163–173.
30. Yamakuchi M, Greer JJ, Cameron SJ, Matsushita K, Morrell CN, Talbot-Fox K, Baldwin WM, III, Lefer DJ, Lowenstein CJ. HMG-CoA reductase inhibitors inhibit endothelial exocytosis and decrease myocardial infarct size. Circ Res. 2005; 96: 1185–1192.
31. Braunersreuther V, Mach F, Steffens S. The specific role of chemokines in atherosclerosis. Thromb Haemost. 2007; 97: 714–721.[Medline] [Order article via Infotrieve]
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