Published online before print October 20, 2005, doi: 10.1161/01.ATV.0000192018.90021.c0
© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
HIV Entry Inhibitor TAK-779 Attenuates Atherogenesis in Low-Density Lipoprotein Receptor–Deficient Mice
From the Division of Biopharmaceutics (E.J.A.v.W., H.H., A.H., P.d.V., T.J.C.v.B., J.K.), Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands; and the Department of Bioorganic Chemistry (T.I.), Graduate School of Pharmaceutical Sciences, Osaka University, and the Department of Oncology (H.F.), Osaka University Graduate School of Medicine, Osaka, Japan.
Correspondence to Eva J.A. van Wanrooij, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail e.van.wanrooij{at}chem.leidenuniv.nl
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Objective— HIV combination therapy using protease inhibitors is associated with elevated plasma levels of atherogenic lipoproteins and increased risk for atherosclerosis. We investigated whether the HIV entry inhibitor TAK-779 affects lipoprotein levels and atherogenesis in low-density lipoprotein receptor-deficient mice. TAK-779 is an antagonist for the chemokine receptors CCR5 and CXCR3, which are expressed on leukocytes, especially T-helper 1 cells, and these receptors may be involved in recruitment of these cells to atherosclerotic plaques.
Methods and Results— TAK-779 treatment of low-density lipoprotein receptor–deficient mice did not elevate the levels of atherogenic lipoproteins, whereas it dramatically reduced atherosclerosis in the aortic root and in the carotid arteries. The number of T cells in the plaque was reduced by 95%, concurrently with a 98% reduction in the relative IFN-
area. TAK-779-treated animals showed a decreased percentage of CD4+ and CD8+ T cells in peripheral blood and in mediastinal lymph nodes compared with control-treated animals.
Conclusions— TAK-779 not only suppresses HIV entry via blockade of CCR5 but also attenuates atherosclerotic lesion formation by blocking the influx of T-helper 1 cells into the plaque. TAK-779 treatment may be especially beneficial for young HIV patients as they face lifelong treatment, and this drug impairs atherogenesis.
The HIV entry inhibitor TAK-779, a CCR5/CXCR3 antagonist, reduced atherogenesis by blocking the influx of Th1 cells into the plaque. We conclude that HIV entry inhibitors, because of their antiatherogenic properties, are preferred for treatment of HIV-positive patients.
Key Words: atherosclerosis • chemokines • HIV • T cells • CCR5
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Leukocyte recruitment into the vessel wall is a key step in atherosclerotic lesion formation, and chemokines are known to regulate this process. Chemokines can be divided into 2 families: the CC receptors, which bind CC chemokines, and the CXC receptors, which bind CXC chemokines.1 CCR5 and CXCR3 are 2 chemokine receptors that are implicated in the migration of activated T-helper (Th)1 cells to the site of inflammation, and both receptors have been suggested as potential targets for the treatment of autoimmune-like diseases.2,3
See page 2448
A 32-bp deletion in the CCR5 gene (CCR5
32) results in a nonfunctional receptor, and individuals that are homozygous for this deletion are resistant to infection with HIV.4,5 Interestingly, it is also shown that this natural deficiency in CCR5 protects individuals from early myocardial infarction and severe coronary artery disease. The ligands for CCR5, RANTES and MIP-1
, have been detected in atherosclerotic plaques of both humans and mice.6–9 Furthermore, inhibition of CCR5/CCR1 using the receptor antagonist met-RANTES attenuates atherosclerosis in low-density lipoprotein receptor (LDLr–/–)-deficient mice.10 Antibody-mediated blockade of CXCR3 results in a decreased recruitment of Th1 cells to the site of inflammation.3
TAK-779 {N,N-dimethyl-N-[4-({[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl}amino)benzyl]-tetrahydro-2H-pyran4-aminium chloride} is a nonpeptide CCR5/CXCR3 antagonist that was developed for the treatment of HIV infection by inhibiting HIV cell entry via CCR5.11–13 TAK-779, however, has also some antiimmunogenic effects. It has been shown to block the influx of CCR5- and CXCR3-positive T cells into inflamed joints in an experimental model for arthritis.14
Both CCR5 and CXCR3 are predominantly expressed on Th1 cells.15 Because atherosclerosis is considered to be a Th1-mediated disease,16,17 treatment with TAK-779 could possibly attenuate atherogenesis by blocking the influx of Th1 cells into the atherosclerotic lesion. Both studies in humans and mice demonstrate an increase in atherosclerotic lesion formation and myocardial infarction in relation to the protease inhibitor treatment in HIV-positive patients.18–22 TAK-779 could, therefore, have a dual function in these patients, because it not only blocks virus entry, but at the same time inhibits the severe side effects of their therapy.
In the present study, we show that treatment of LDLr-deficient (LDLr–/–) mice with TAK-779 attenuates atherosclerotic lesion formation. TAK-779 treatment may, therefore, serve as a new convenient treatment of HIV infection and, at the same, time attenuate atherosclerotic lesion formation, in contrast to the combination therapy now available with protease inhibitors.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animal Experiments
Female LDLr–/– mice, 15 weeks of age (n=10/group), were put on a Western-type diet containing 0.25% cholesterol and 15% cocoa butter 2 weeks before collar placement. Silastic collars (0.3-mm ID, Dow Corning) were placed to induce atherosclerosis as described previously.23,24
Mice were treated immediately after collar placement with an injection of 150 µg TAK-779 in 100 µL of 5% mannitol (wt/vol) SC every other day during 6 weeks, after which mice were anesthetized and subsequently euthanized during tissue harvesting (5% mannitol was used as a control). In a second experiment, female LDLr–/– (mice n=10/group) were fed a Western-type diet, and TAK-779 treatment was started simultaneously.
Histological Analysis
Cryosections were stained with hematoxylin (Sigma Diagnostics) and eosin (Merck diagnostics). Corresponding sections were stained with antibodies directed against a macrophage-specific antigen (MOMA-2, polyclonal rat IgG2b, Research Diagnostics), -smooth muscle cell actin (monoclonal mouse IgG2a, clone 1A4, Sigma Diagnostics), IFN- (rat IgG1, clone XMG1.2, BD Pharmingen), or CD3 (molecular complex 17A2, BD Pharmingen) for 2 hours. As secondary antibodies (1 hour incubation), goat antirat IgG alkaline phosphatase conjugate (Nordic) with nitro blue tetrazolium and 5-bromo-4-chloro-3-indolyl phosphate as enzyme substrates or biotinylated goat antirat polyclonal Ig (BD Pharmingen) was used in combination with streptABC complex (DAKO), with nova red as an enzyme substrate (Vector Laboratories). Collagen was visualized by picosirius red (Direct red 80) and lipids by Oil red O staining.
Serum Lipid Levels
Concentrations of serum cholesterol and triglycerides were determined using enzymatic colorimetric procedures.
Real-Time PCR Assays
Please see http://atvb.ahajournals.org for detailed protocol.
Flow Cytometry
Please see http://atvb.ahajournals.org for detailed protocol.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
mRNA Expression in Spleen of CCR5, CXCR3, and Their Ligands
CCR5 and CXCR3 are chemokine receptors that are mainly expressed on Th1 cells.25,26 The spleen plays a central role in the immune system and is exposed to circulating antigens associated with atherosclerosis, such as oxidized LDL. We examined the mRNA expression of CCR5 and CXCR3 and their ligands in the spleen in LDLr–/– mice on a Western-type diet (Figure 1).
|
After 6 weeks of the diet, CCR5 relative mRNA expression in the spleen was significantly upregulated 2.4-fold (1.0±0.06 versus 2.4±0.21; P=0.01). The expression of CXCR3 was not differentially regulated during the first 6 weeks of feeding a Western-type diet and atherosclerotic lesion formation. Both CCR5 and CXCR3 were downregulated in the spleen in later stages of atherosclerotic lesion formation (> 9 weeks of Western-type diet). RANTES and MIP-1, established ligands for CCR5, were both significantly upregulated after 6 weeks of the Western-type diet. This coincides with the regulation pattern of CCR5 and monocyte chemotactic protein 1 (MCP-1). CXCL10, a ligand specific for CXCR3 was downregulated after 9 weeks of the Western-type diet and showed no regulatory similarity with the other ligands.
TAK-779 Reduces Atherogenesis in LDLr–/– Mice Without Altering Cholesterol Levels
Two different experiments were performed to study the effect of TAK-779 on atherogenesis. After 2 weeks of Western-type diet, LDLr–/– mice were equipped with collars and were treated with TAK-779 or control treated for 6 weeks. Yang et al14 showed that administration of 150 µg per mouse every other day was sufficient to induce the maximum blocking effect. No difference in cholesterol levels and lipoprotein concentration could be observed between the control and TAK-779-treated group (Figure I, available online at http://atvb.ahajournals.org). Figure 2 shows representative sections of TAK-779-treated (Figure 2d) and control-treated (Figure 2e) mice. Lesion size significantly decreased by 68% on treatment with TAK-779 (18384±3370 µm2 versus 5926±1842 µm2; P=0.004; Figure 2a), intima-media ratio decreased by 49% (0.46±0.07 versus 0.26±0.06; Figure 2b), and also the relevant clinical parameter, intima lumen ratio, decreased significantly by 56% (0.26±0.04 versus 0.11±0.03; P=0.01; Figure 2c).
|
The general composition of the carotid lesions of TAK-779-treated mice was not altered compared with control-treated mice (Figure II, available online at http://atvb.ahajournals.org). The relative MOMA-2-stained area was comparable in control (IIB) and TAK-779-treated animals (IIC; 0.265±0.05 versus 0.252±0.06; P=0.88). Collagen content of the plaque determined by picosirius red staining showed no difference between control (IIE) and treated mice (IIF; 0.095±0.03 versus 0.101±0.03; P=0.69). TAK-779 treatment did not affect the relative smooth muscle cell area [0.084±0.016 (IIH) versus 0.078±0.011 (Iii)].
In a second experimental setup, Western-type diet and TAK-779 treatment were started simultaneously, and 6 weeks later LDLr–/– mice were euthanized. Atherosclerosis in the aortic valves was decreased by 40% in TAK-779-treated mice compared with control mice without altering the relative macrophage content (Figure III, available online at http://atvb.ahajournals.org).
TAK-779 Treatment Impairs the Influx of Th1 T Cells to the Atherosclerotic Plaque
Both CCR5 and CXCR3 are expressed on Th1 cells and are implicated in the migration of these cells to their site of action, and treatment with TAK-779 may block the migration of Th1 cells into the atherosclerotic plaque. We performed a staining for CD3 (Figure 3a), a general T cell marker, and scored for positive cells in both the plaque and the adventitia. A vast and significant decrease was observed in the number of T cells in the plaque and adventitia of TAK-779-treated mice compared with control (plaque 0.53±0.31 versus 0.03±0.03; P=0.04; adventitia 4.98±0.63 versus 2.01±0.38; P=0.0007). The reduction in T cells resulted in a decreased expression of the Th1-specific marker IFN-, and a significant reduction of 98% was observed in the IFN--positive area in TAK-779-treated animals (Figure 3d) compared with control (Figure 3e) (0.55%±0.21% versus 0.01%±0.0004%; P=0.013).
|
TAK-779 Reduces T Cell Counts in LDLr–/– Mice
To investigate whether T cell numbers were affected during atherogenesis in TAK-779-treated mice versus control treated mice, lymphocytes were harvested from blood, from mediastinal lymph nodes, which drain from the aortic arch, and from spleen 6 weeks after the start of the Western-type diet. The percentages of CD4+ and CD8+ T cells were determined by flow cytometric analysis. Figure 4a shows representative dot plots for control-treated mice (top 3 panels) and TAK-779-treated mice (bottom 3 panels) on a Western-type diet. A vast decrease in the percentage of CD4+ T cells in peripheral blood (21.6±3.11% versus 10.46±1.57%; P=0.02) and a modest decrease in lymph nodes (35.3±2.5% versus 26.9±4%; P=0.14) was observed in the TAK-779-treated group. In contrast, the CD4+ population was significantly increased in the spleen of the TAK-779-treated mice (9.6±1.22% versus 13.5±0.9%; P=0.03; Figure 4b). An even more pronounced decrease was observed in the CD8+ T cell population. In the circulation, the percentage of CD8+ T cells decreased from 10.2±1.8% in the control group to 3.8±0.7% in the treated group (P=0.01). In the mediastinal lymph nodes draining from the aortic arch, a reduction of 34% in the number of CD8+ cells was observed (21.4±0.52% versus 14.6±2.0%, P=0.02; Figure 4c). No significant differences in total white blood cell counts were observed between control and treated mice.
|
) compared with control (
). In the spleen, the percentage of CD4-positive cells is increased in the treated group.
Inflammatory Status in the Spleen After TAK-779 Treatment
After 6 weeks of simultaneous Western-type diet feeding and TAK-779 treatment, the mRNA expression of CCR5 and CXCR3 was determined (Figure 5). CCR5 expression was 1.9-fold increased in TAK-779-treated mice (P=0.02), whereas the expression of CXCR3 remained unchanged. The expression of CCR2 was highly elevated in the spleen on TAK-779 treatment. The splenic mRNA levels for MIP-1, RANTES, and CXCL10, which bind to CCR5 and CXCR3, respectively, were not affected by TAK-779 treatment, whereas the expression of MCP-1, a ligand for CCR2, was significantly upregulated by 8.1-fold. We also determined the expression of some cytokines that are important in the Th1/Th2 balance. Interleukin (IL)12, a general Th1 stimulatory IL, is 2.8-fold upregulated in the spleen of TAK-779-treated mice as compared with control-treated mice, whereas the Th2 IL-4 is 3.2-fold upregulated. This results in an unaffected Th1/Th2 balance on TAK-779 treatment, and the observed increase in splenic cytokine expression might be explained by the increased number of CD4+ T cells in the spleen (Figure 4).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Infiltration of mononuclear cells into the vessel wall is an important hallmark of atherosclerosis. It has become clear that, next to macrophages, T lymphocytes are present in the atherosclerotic plaque and exert a significant role in plaque progression. The majority of these T cells are CD4 positive. Activation of CD4+ T cells via MHC class II on antigen-presenting cells results in the release of cytokines and the expression of several surface markers. Activated CD4+ T cells can be divided in 2 distinct categories based on their phenotype. Th1 cells secrete IFN-
, IL-2, and tumor necrosis factor . Th2 cells produce IL-4, IL-5, and IL-13. Because atherosclerosis is considered to be a Th1-mediated disease,16,17 modulation of the activation and migration of Th1 T cells provides an attractive therapeutic possibility.
CCR5 and CXCR3 are chemokine receptors that are both primarily expressed on Th1 T cells.15 A putative role for CCR5 and CXCR3 in atherogenesis is implicated by studies in which a mutation in the CCR5 sequence (32 mutation) was associated with a reduced incidence in coronary artery disease.6,7 Furthermore, antagonizing CCR5 using met-RANTES resulted in reduced atherosclerotic lesion formation.10
The HIV entry inhibitor TAK-779 is a CCR5 and CXCR3 antagonist in mice, and TAK-779 reduces autoimmune responses by interfering with the migration of Th1 cells into the inflamed tissue.14 We argue that TAK-779 may, therefore, also affect atherogenesis in a similar way. Because the current treatment for HIV patients is associated with accelerated atherosclerosis, an anti-HIV drug that reduces atherosclerosis would be of great importance.
We first examined the expression of CCR5 and CXCR3 in the spleen of LDLr–/– mice during a Western-type diet feeding. CXCR3 was not differentially regulated in the spleen during the first 6 weeks of the atherogenic diet, whereas CCR5 showed a significant upregulation in this period. The ligands of CCR5, RANTES, and MIP-1 have been detected in atherosclerotic plaques, and these molecules were also upregulated at 6 weeks of Western-type diet feeding in the spleen.8 No distinct regulatory pattern could be observed for the ligands of CXCR3, INF--inducible protein-10, and CXCL10. This suggests that CCR5 may have a more prominent role in the response of the immune system toward elevated cholesterol levels and atherogenesis.
In our studies, the synthetic low molecular weight CCR5/CXCR3 antagonist TAK-779 was used to assess the role of these receptors in atherosclerosis. Treatment with this potential HIV entry inhibitor appeared to reduce plaque formation in the carotid artery with 68% and lesion formation in the aortic root with 40%. These findings are in line with a study by Veillard et al,10 who used met-RANTES to antagonize CCR5 and CCR-1 and observed a decrease in lesion formation as a result of reduced infiltration of mononuclear cells into the lesion. In contrast, disruption of the mouse CCR5 gene has no effect on early lesion formation in apoE-deficient mice.28 Because these mice lack CCR5 throughout their development, it may be that impaired T cell migration attributable to CCR5 disruption is counterbalanced by a compensatory chemokine receptor-mediated mechanism, such as CCR-2/MCP-1.
The expression of CCR5 and CXCR3 has been well characterized on CD4+ T cells, and both chemokine receptors are preferentially expressed on the Th1 cell subset.25,26 Limited expression of CCR5 is also reported on CD8+ cells, human vascular smooth muscle cells, and macrophages.30,31
Our data show that the relative macrophage content of the atherosclerotic plaques did not differ between TAK-779-treated and control-treated mice. This implies that migration of macrophages into the intima is not impaired by CCR5/CXCR3 blockade by TAK-779. Therefore, decreased lesion formation is more likely to be explained by diminished migration of T cells toward the sites of atherogenesis. This is additionally supported by the significantly decreased number of CD3+ T cells in the plaque, as well as in the adventitia in TAK-779-treated animals. We also observed that the number of CD4+ and CD8+ T cells in blood and draining lymph nodes were significantly decreased in TAK-779-treated animals. Simultaneously, the percentage of CD4+ T cells in the spleen is increased, suggesting that these T cells are retained in the spleen on TAK-779 treatment.
Veillard et al10 described that antagonizing CCR1 and CCR5 with met-RANTES results in decreased macrophage and T cell influx into the atherosclerotic lesion, in contrast to antagonizing CCR5/CXCR3 with TAK-779, which only affects T cell influx. This difference may be explained by the fact that met-RANTES antagonizes CCR1, which is expressed at high levels on macrophages, in contrast to CCR5 and CXCR3. TAK-779 is, therefore, more selective in antagonizing Th1 T cells, leaving macrophage recruitment mostly intact. We used an in vitro setup to test the effect of TAK-779 on macrophage adhesion to lipopolysaccharide-stimulated endothelial cells. No dose-effect relationship for TAK-779 incubation of macrophages on endothelial adhesion was observed (data not shown). This additionally strengthens our findings that there is no major effect on macrophage adhesion and infiltration in TAK-779-treated animals.
Local T cells secrete cytokines, which, in turn, activate and attract other inflammatory cells and, therefore, stimulate the inflammatory process. Because CCR5 and CXCR3 are most strongly expressed on Th1 cells, it is expected that mice treated with TAK-779 show smaller amounts of Th1 cytokines in the atherosclerotic plaque. We stained atherosclerotic plaque sections of control and treated mice for IFN-, a Th1 marker. In plaques of treated animals, the relative IFN- area was decreased by 98%, indicating that IFN- production by Th1 cells was almost completely absent on TAK-779 treatment.
Our data show that the TAK-779 blockade resulted in a marked upregulation of CCR2/MCP-1in the spleen, which coincides with an upregulation of CCR5 in the spleen in comparison with control mice. This may be explained by the fact that CCR2 and CCR5 coexist in the same lipid raft domain, and both receptors share a migratory function.29 Inhibition of CCR5 is then compensated by an upregulation of CCR2 to sustain migratory capacity.
Baba et al.11 have shown that TAK-779 has some affinity for CCR2b in humans, but this is 100-fold lower in comparison with CCR5. In addition, TAK-779 is not able to bind human CXCR3. Therefore, it is likely that TAK-779 exerts its action by inhibiting CCR5 function in humans. We observed similar effects in our study in mice, because the expression of CXCR3 in the spleen of mice treated with TAK-779 is not increased, in contrast with the expression of CCR5, thus implying a dominant role for CCR5 as a target of TAK-779.
The increase in individual expression of the different chemokine receptors, combined with the unaltered Th1:Th2 ratio, supports the theory that TAK-779 targets CCR5 and impairs T cell migration to the site of action, the atherosclerotic plaque, and does not alter the general inflammatory status of the animals.
Combination therapy, which is commonly used to treat HIV patients, has been shown to lead to elevated serum levels of the atherogenic lipoproteins LDL and VLDL, which result in a higher incidence in cardiovascular disease.27 We now show that TAK-779, a novel HIV entry inhibitor, does not elevate serum total cholesterol levels or triglyceride levels. More important, no increase in atherogenic lipoprotein levels was observed in the blood of TAK-779-treated animals, and a decrease was observed in atherosclerotic lesion formation. This is in contrast with patients and animal models treated with protease inhibitors.
In summary, the use of HIV entry inhibitors in the long-term treatment of HIV would be preferential over the combination therapy used now. It achieves long-term suppression of the virus and, as shown in this study, retained atherosclerotic lesion formation by blocking the influx of Th1 cells in the atherosclerotic plaque. This finding is primarily beneficial for young HIV patients, because they face a lifelong treatment and are currently confronted with the severe side effect of heart disease.
|
Acknowledgments |
|---|
This study was supported by grant 2000.198 from the Netherlands Heart Foundation and NWO grant 050-10-014. J.K. is an Established Investigator of the Netherlands Heart Foundation (grant 2000D040).
Received April 12, 2005; accepted September 28, 2005.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Rottman JB, Ganley KP, Williams K, Wu L, Mackay CR, Ringler DJ. Cellular localization of the chemokine receptor CCR5. Correlation to cellular targets of HIV-1 infection. Am J Pathol. 1997; 151: 1341–1351.[Abstract]
- Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Mackay CR. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest. 1998; 101: 746–754.[Medline] [Order article via Infotrieve]
- Xie JH, Nomura N, Lu M, Chen SL, Koch GE, Weng Y, Rosa R, Di Salvo J, Mudgett J, Peterson LB, Wicker LS, DeMartino JA. Antibody-mediated blockade of the CXCR3 chemokine receptor results in diminished recruitment of T helper 1 cells into sites of inflammation. J Leukoc Biol. 2003; 73: 771–780.
[Abstract/Free Full Text] - Huang Y, Paxton WA, Wolinsky SM, Neumann AU, Zhang L, He T, Kang S, Ceradini D, Jin Z, Yazdanbakhsh K, Kunstman K, Erickson D, Dragon E, Landau NR, Phair J, Ho DD, Koup RA. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med. 1996; 2: 1240–1243.[CrossRef][Medline] [Order article via Infotrieve]
- Balotta C, Bagnarelli P, Violin M, Ridolfo AL, Zhou D, Berlusconi A, Corvasce S, Corbellino M, Clementi M, Clerici M, Moroni M, Galli M. Homozygous delta 32 deletion of the CCR-5 chemokine receptor gene in an HIV-1-infected patient. Aids. 1997; 11: F67–F71.[CrossRef][Medline] [Order article via Infotrieve]
- Gonzalez P, Alvarez R, Batalla A, Reguero JR, Alvarez V, Astudillo A, Cubero GI, Cortina A, Coto E. Genetic variation at the chemokine receptors CCR5/CCR2 in myocardial infarction. Genes Immun. 2001; 2: 191–195.[CrossRef][Medline] [Order article via Infotrieve]
- Szalai C, Duba J, Prohaszka Z, Kalina A, Szabo T, Nagy B, Horvath L, Csaszar A. Involvement of polymorphisms in the chemokine system in the susceptibility for coronary artery disease (CAD). Coincidence of elevated Lp(a) and MCP-1–2518 G/G genotype in CAD patients. Atherosclerosis. 2001; 158: 233–239.[CrossRef][Medline] [Order article via Infotrieve]
- Wilcox JN, Nelken NA, Coughlin SR, Gordon D, Schall TJ. Local expression of inflammatory cytokines in human atherosclerotic plaques. J Atheroscler Thromb. 1994; 1 (Suppl 1): S10–S13.
- von Hundelshausen P, Weber KS, Huo Y, Proudfoot AE, Nelson PJ, Ley K, Weber C. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation. 2001; 103: 1772–1777.
[Abstract/Free Full Text] - Veillard NR, Kwak B, Pelli G, Mulhaupt F, James RW, Proudfoot AE, Mach F. Antagonism of RANTES receptors reduces atherosclerotic plaque formation in mice. Circ Res. 2004; 94: 253–261.
[Abstract/Free Full Text] - Baba M, Nishimura O, Kanzaki N, Okamoto M, Sawada H, Iizawa Y, Shiraishi M, Aramaki Y, Okonogi K, Ogawa Y, Meguro K, Fujino M. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc Natl Acad Sci U S A. 1999; 96: 5698–5703.
[Abstract/Free Full Text] - Gao P, Zhou XY, Yashiro-Ohtani Y, Yang YF, Sugimoto N, Ono S, Nakanishi T, Obika S, Imanishi T, Egawa T, Nagasawa T, Fujiwara H, Hamaoka T. The unique target specificity of a nonpeptide chemokine receptor antagonist: selective blockade of two Th1 chemokine receptors CCR5 and CXCR3. J Leukoc Biol. 2003; 73: 273–280.
[Abstract/Free Full Text] - Shiraishi M, Aramaki Y, Seto M, Imoto H, Nishikawa Y, Kanzaki N, Okamoto M, Sawada H, Nishimura O, Baba M, Fujino M. Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety. J Med Chem. 2000; 43: 2049–2063.[CrossRef][Medline] [Order article via Infotrieve]
- Yang YF, Mukai T, Gao P, Yamaguchi N, Ono S, Iwaki H, Obika S, Imanishi T, Tsujimura T, Hamaoka T, Fujiwara H. A non-peptide CCR5 antagonist inhibits collagen-induced arthritis by modulating T cell migration without affecting anti-collagen T cell responses. Eur J Immunol. 2002; 32: 2124–2132.[CrossRef][Medline] [Order article via Infotrieve]
- Sallusto F, Lanzavecchia A, Mackay CR. Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses. Immunol Today. 1998; 19: 568–574.[CrossRef][Medline] [Order article via Infotrieve]
- Benagiano M, Azzurri A, Ciervo A, Amedei A, Tamburini C, Ferrari M, Telford JL, Baldari CT, Romagnani S, Cassone A, D’Elios MM, Del Prete G. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions. Proc Natl Acad Sci U S A. 2003; 100: 6658–6663.
[Abstract/Free Full Text] - Mallat Z, Gojova A, Brun V, Esposito B, Fournier N, Cottrez F, Tedgui A, Groux H. Induction of a regulatory T cell type 1 response reduces the development of atherosclerosis in apolipoprotein E-knockout mice. Circulation. 2003; 108: 1232–1237.
[Abstract/Free Full Text] - Varriale P, Saravi G, Hernandez E, Carbon F. Acute myocardial infarction in patients infected with human immunodeficiency virus. Am Heart J. 2004; 147: 55–59.[CrossRef][Medline] [Order article via Infotrieve]
- d’Arminio A, Sabin CA, Phillips AN, Reiss P, Weber R, Kirk O, El-Sadr W, De Wit S, Mateu S, Petoumenos K, Dabis F, Pradier C, Morfeldt L, Lundgren JD, Friis-Moller N. Cardio- and cerebrovascular events in HIV-infected persons. Aids. 2004; 18: 1811–1817.[CrossRef][Medline] [Order article via Infotrieve]
- Barbaro G. Cardiovascular manifestations of HIV infection. Circulation. 2002; 106: 1420–1425.
[Free Full Text] - Tabib A, Leroux C, Mornex JF, Loire R. Accelerated coronary atherosclerosis and arteriosclerosis in young human-immunodeficiency-virus-positive patients. Coron Artery Dis. 2000; 11: 41–46.[CrossRef][Medline] [Order article via Infotrieve]
- Dressman J, Kincer J, Matveev SV, Guo L, Greenberg RN, Guerin T, Meade D, Li X-A, Zhu W, Uittenbogaard A, Wilson ME, Smart EJ. HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesteryl ester accumulation in macrophages. J Clin Invest. 2003; 111: 389–397.[CrossRef][Medline] [Order article via Infotrieve]
- von der Thusen JH, van Berkel TJ, Biessen EA. Induction of rapid atherogenesis by perivascular carotid collar placement in apolipoprotein E-deficient and low-density lipoprotein receptor-deficient mice. Circulation. 2001; 103: 1164–1170.
[Abstract/Free Full Text] - Herijgers N, Van Eck M, Groot PH, Hoogerbrugge PM, Van Berkel TJ. Effect of bone marrow transplantation on lipoprotein metabolism and atherosclerosis in LDL receptor-knockout mice. Arterioscler Thromb Vasc Biol. 1997; 17: 1995–2003.
[Abstract/Free Full Text] - Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A, Sozzani S, Allavena P, Gray PA, Mantovani A, Sinigaglia F. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med. 1998; 187: 129–134.
[Abstract/Free Full Text] - Campbell JD, HayGlass KT. T cell chemokine receptor expression in human Th1- and Th2-associated diseases. Arch Immunol Ther Exp (Warsz). 2000; 48: 451–456.[Medline] [Order article via Infotrieve]
- Periard D, Telenti A, Sudre P, Cheseaux JJ, Halfon P, Reymond MJ, Marcovina SM, Glauser MP, Nicod P, Darioli R, Mooser V. Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation. 1999; 100: 700–705.
[Abstract/Free Full Text] - Kuziel WA, Dawson TC, Quinones M, Garavito E, Chenaux G, Ahuja SS, Reddick RL, Maeda N. CCR5 deficiency is not protective in the early stages of atherogenesis in apoE knockout mice. Atherosclerosis. 2003; 167: 25–32.[CrossRef][Medline] [Order article via Infotrieve]
- Mellado M, Rodriguez-Frade JM, Vila-Coro AJ, Fernandez S, Martin de Ana A, Jones DR, Toran JL, Martinez AC. Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. Embo J. 2001; 20: 2497–2507.[CrossRef][Medline] [Order article via Infotrieve]
- Fukada K, Sobao Y, Tomiyama H, Oka S, Takiguchi M. Functional expression of the chemokine receptor CCR5 on virus epitope-specific memory and effector CD8+ T cells. J Immunol. 2002; 168: 2225–2232.
[Abstract/Free Full Text] - Schecter AD, Calderon TM, Berman AB, McManus CM, Fallon JT, Rossikhina M, Zhao W, Christ G, Berman JW, Taubman MB. Human vascular smooth muscle cells possess functional CCR5. J Biol Chem. 2000; 275: 5466–5471.
[Abstract/Free Full Text]
Related Article:
- Killing Two Birds With One Stone: Targeting Chemokine Receptors in Atherosclerosis and HIV Infection
- Christian Weber
Arterioscler. Thromb. Vasc. Biol. 2005 25: 2448-2450.[Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  V. Braunersreuther, S. Steffens, C. Arnaud, G. Pelli, F. Burger, A. Proudfoot, and F. Mach A Novel RANTES Antagonist Prevents Progression of Established Atherosclerotic Lesions in Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2008; 28(6): 1090 - 1096. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J.A. van Wanrooij, S. C.A. de Jager, T. van Es, P. de Vos, H. L. Birch, D. A. Owen, R. J. Watson, E. A.L. Biessen, G. A. Chapman, T. J.C. van Berkel, et al. CXCR3 Antagonist NBI-74330 Attenuates Atherosclerotic Plaque Formation in LDL Receptor-Deficient Mice Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 251 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. I. van Leuven, R. Franssen, J. J. Kastelein, M. Levi, E. S. G. Stroes, and P. P. Tak Systemic inflammation as a risk factor for atherothrombosis Rheumatology, January 1, 2008; 47(1): 3 - 7. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Hauer, G. H.M. van Puijvelde, N. Peterse, P. de Vos, V. van Weel, E. J.A. van Wanrooij, E. A.L. Biessen, P. H.A. Quax, A. G. Niethammer, R. A. Reisfeld, et al. Vaccination Against VEGFR2 Attenuates Initiation and Progression of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., September 1, 2007; 27(9): 2050 - 2057. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Wu, S. Ghosh, X. D. Perrard, L. Feng, G. E. Garcia, J. L. Perrard, J. F. Sweeney, L. E. Peterson, L. Chan, C. W. Smith, et al. T-Cell Accumulation and Regulated on Activation, Normal T Cell Expressed and Secreted Upregulation in Adipose Tissue in Obesity Circulation, February 27, 2007; 115(8): 1029 - 1038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Braunersreuther, A. Zernecke, C. Arnaud, E. A. Liehn, S. Steffens, E. Shagdarsuren, K. Bidzhekov, F. Burger, G. Pelli, B. Luckow, et al. Ccr5 But Not Ccr1 Deficiency Reduces Development of Diet-Induced Atherosclerosis in Mice Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 373 - 379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Weber Killing Two Birds With One Stone: Targeting Chemokine Receptors in Atherosclerosis and HIV Infection Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2448 - 2450. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||