Plasma Levels Of Monocyte Chemoattractant Protein-1 Research Articles

Coronary collaterals: The role of MCP-1 during the early phase of acute myocardial infarction

Background The collateral growth (arteriogenesis) of an individual may vary from complete to absent during the early phase of acute myocardial infarction (AMI). However, the mechanisms underlying the large differences in the extent and adequacy of collateralization remain unclear. We hypothesized that shear stress-induced activation of monocyte chemoattractant protein-1 could potently contribute to the development of coronary collaterals during the early phase of AMI. Methods We enrolled forty patients with AMI who did not receive reperfusion therapy within 24 h after the onset of chest pain and who also underwent coronary angiography (CAG) from 1 to 7 days after admission (mean duration: 3.6 ± 2.2 days). The grades of the collateral development were angiographically defined and grouped according to the grade of collaterals as absent (score 0, n = 20) or well-developed (score 2, n = 20) collateral circulation. The plasma concentrations of vascular endothelial growth factor (VEGF), endostatin, monocyte chemoattractant protein-1 (MCP-1), and stromal cell-derived factor-1 (SDF-1) were assessed by enzyme-linked immunosorbent assay and then these values were compared between the two groups. Results There were no differences in the demographic and angiographic characteristics except for the number of total occlusion in culprit lesion. The plasma MCP-1 levels were significantly higher in the group with well-developed collateral circulation compared to the group with absent collateral circulation (262 ± 216 vs. 151 ± 88 pg/ml, respectively, p = 0.043). However, the plasma levels of VEGF, endostatin and SDF-1 were not different on comparisons between the groups (VEGF; 369 ± 377 vs. 324 ± 363 pg/ml, endostatin; 1.74 ± 1.71 vs. 1.49 ± 1.15 ng/ml, SDF-1; 1806 ± 508 vs. 2091 ± 772 pg/ml, respectively). Conclusion During the early phase of AMI, the plasma levels of MCP-1 were significantly increased in the patients with well-developed collateral circulation as compared to those patients with absent collateral circulation. These findings suggested that the shear stress-induced overexpression of MCP-1 contributes significantly to the development of coronary collaterals during the early phase of AMI.

Association of sICAM-1 and MCP-1 with coronary artery calcification in families enriched for coronary heart disease or hypertension: the NHLBI Family Heart Study

BackgroundData accumulated from mouse studies and in vitro studies of human arteries support the notion that soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1) play important roles in the inflammation process involved in atherosclerosis. However, at the population level, the utility of sICAM-1 and MCP-1 as biomarkers for subclinical atherosclerosis is less clear. In the follow-up exam of the NHLBI Family Heart Study, we evaluated whether plasma levels of sICAM-1 and MCP-1 were associated with coronary artery calcification (CAC), a measure of the burden of coronary atherosclerosis.MethodsCAC was measured using the Agatston score with multidetector computed tomography. Information on CAC and MCP-1 was obtained in 2246 whites and 470 African Americans (mean age 55 years) without a history of coronary heart disease (CHD). Information on sICAM-1 was obtained for white participants only.ResultsIn whites, after adjustment for age and gender, the odds ratios (ORs) of CAC (CAC > 0) associated with the second, third, fourth, and fifth quintiles of sICAM-1 compared to the first quintile were 1.22 (95% confidence interval [CI]: 0.91–1.63), 1.15 (0.84–1.58), 1.49 (1.09–2.05), and 1.72 (1.26–2.36) (p = 0.0005 for trend test), respectively. The corresponding ORs for the second to fifth quintiles of MCP-1 were 1.26 (0.92–1.73), 0.99 (0.73–1.34), 1.42 (1.03–1.96), and 2.00 (1.43–2.79) (p < 0.0001 for trend test), respectively. In multivariable analysis that additionally adjusted for other CHD risk factors, the association of CAC with sICAM-1 and MCP-1 was attenuated and no longer statistically significant. In African Americans, the age and gender-adjusted ORs of CAC associated with the second and third tertiles of MCP-1 compared to the first tertile were 1.16 (0.64–2.08) and 1.25 (0.70–2.23) (p = 0.44 for trend test), respectively. This result did not change materially after additional adjustment for other CHD risk factors. Test of race interaction showed that the magnitude of association between MCP-1 and CAC did not differ significantly between African Americans and whites. Similar results were obtained when CAC ≥ 10 was analyzed as an outcome for both MCP-1 and sICAM-1.ConclusionThis study suggests that sICAM-1 and MCP-1 are biomarkers of coronary atherosclerotic burden and their association with CAC was mainly driven by established CHD risk factors.

Folic acid reduces chemokine MCP-1 release and expression in rats with hyperhomocystinemia

This study aimed to investigate the effects of folate on the monocyte chemoattractant protein-1 (MCP-1) expression and release in rats with hyperhomocystinemia induced by ingestion of excess methionine. Thirty male Sprague-Dawley rats (200+/-20 g) were randomly divided into three groups (n=10 for each group): control group (Control), high-homocystinemia (Hhcy) group, and folate treatment (FA) group. They were fed with a normal regular diet, enriched by 1.7% methionine plus 1.7% methionine and 0.006% folate for 45 days. Our study showed the following: (a) A high methionine diet for 45 days is sufficient to induce hyperhomocystinemia; folate supplementation to the rats fed the high-methionine diet prevented an elevation homocysteine (Hcy) levels in the blood (P<.01). (b) Compared with the Control group, the Hhcy group had elevated plasma levels of MCP-1, and Hcy was significantly correlated with MCP-1 (P<.05). (c) The protein and mRNA expression of MCP-1 in the aorta was higher in rats from the Hhcy group than in rats from the Control group. (d) Most important, after folic acid supplementation, the lowering of Hcy levels was accompanied by a marked reduction of MCP-1 expressed in aortae and released from plasma and peripheral blood mononuclear cells (PBMCs) stimulated by oxidized low-density lipoprotein (P<.05, P<.01). Folic acid supplementation not only can blunt the rise in Hcy and reduce MCP-1 released from both plasma and PBMCs of rats with hyperhomocystinemia but also can downgrade MCP-1 expression in the aorta of rats with hyperhomocystinemia.

The Nitric Oxide-Donating Pravastatin Derivative, NCX 6550 [(1S-[1α(βS*, δS*), 2α, 6α, 8β-(R*), 8aα]]-1,2,6,7,8,8a-Hexahydro-β, δ, 6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphtalene-heptanoic Acid 4-(Nitrooxy)butyl Ester)], Reduces Splenocyte Adhesion and Reactive Oxygen Species Generation in Normal and Atherosclerotic Mice

Statins possess anti-inflammatory effects that may contribute to their ability to slow atherogenesis, whereas nitric oxide (NO) also influences inflammatory cell adhesion. This study aimed to determine whether a novel NO-donating pravastatin derivative, NCX 6550 [(1S-[1alpha(betaS*,deltaS*),2alpha,6alpha,8beta-(R*),8a alpha]]-1,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-heptanoic acid 4-(nitrooxy)butyl ester)], has greater anti-inflammatory properties compared with pravastatin in normal and atherosclerotic apolipoprotein E receptor knockout (ApoE-/-) mice. C57BL/6 and ApoE-/- mice were administered pravastatin (40 mg/kg), NCX 6550 (48.5 mg/kg), or vehicle orally for 5 days. Ex vivo studies assessed splenocyte adhesion to arterial segments and splenocyte reactive oxygen species (ROS) generation. NCX 6550 significantly reduced splenocyte adhesion to artery segments in both C57BL/6 (8.8 +/- 1.9% versus 16.6 +/- 6.7% adhesion; P < 0.05) and ApoE-/- mice (9.3 +/- 2.9% versus 23.4 +/- 4.6% adhesion; P < 0.05) concomitant with an inhibition of endothelial intercellular adhesion molecule-1 expression. NCX 6550 also significantly reduced phorbol 12-myristate 13-acetate-induced ROS production that was enhanced in isolated ApoE-/- splenocytes. Conversely, pravastatin had no significant effects on adhesion in normal or ApoE-/- mice but reduced the enhanced ROS production from ApoE-/- splenocytes. In separate groups of ApoE-/- mice, NCX 6550 significantly enhanced endothelium-dependent relaxation to carbachol in aortic segments precon-tracted with phenylephrine (-logEC(50), 6.37 +/- 0.37) compared with both vehicle-treated (-logEC50, 5.81 +/- 0.15; P < 0.001) and pravastatin-treated (-logEC50, 5.57 +/- 0.45; P < 0.05) mice. NCX 6550 also significantly reduced plasma monocyte chemoattractant protein-1 levels (648.8 pg/ml) compared with both vehicle (1191.1 pg/ml; P < 0.001) and pravastatin (847 +/- 71.0 pg/ml; P < 0.05) treatment. These data show that NCX 6550 exerts superior anti-inflammatory actions compared with pravastatin, possibly through NO-related mechanisms.

Ethanol beverages containing polyphenols decrease nuclear factor kappa-B activation in mononuclear cells and circulating MCP-1 concentrations in healthy volunteers during a fat-enriched diet

Aims Different epidemiological studies have demonstrated that some ethanol containing beverages intake could be associated with a reduction of cardiovascular mortality, effect attributed in part to its antioxidant properties. Nuclear factor-kappa B (NF-kappaB) is a redox sensitive transcription factor implicated in the pathogenesis of atherosclerosis. We have examined the effect of four different ethanol containing beverages on the activation of NF-kappaB in peripheral blood mononuclear cells (PBMC) and circulating concentrations of monocyte chemoattractant protein-1 (MCP-1) in healthy volunteers receiving a fat-enriched diet. Methods and results Sixteen volunteers received 16 g/m 2 of ethanol in form of red wine, spirits (vodka, rum, and brandy) or no ethanol intake along with a fat-enriched diet during 5 days and all of them took all alcohols at different periods. NF-kappaB activation (electrophoretic mobility shift assay) and circulating MCP-1 levels (ELISA) were examined in blood samples taken before and after 5 days of ethanol intake. Subjects receiving a fat-enriched diet had increased NF-kappaB activation in PBMC at day 5. Furthermore, MCP-1 levels were increased in plasma at day 5. Red wine intake and some ethanol beverages containing polyphenols (brandy and rum) prevented NF-kappaB activation and decreased MCP-1 release. Conclusion Consumption of moderate amounts of alcoholic drinks containing polyphenols decreases NF-kappaB activation in PBMCs and MCP-1 plasma levels during a fat-enriched diet. Our results provide additional evidence of the anti-inflammatory effects of some ethanol containing beverages, further supporting the idea that its moderate consumption may help to reduce overall cardiovascular mortality.

MCP-1 chemokine receptor CCR2 is decreased on circulating monocytes in sporadic amyotrophic lateral sclerosis (sALS)

Recent studies suggest that monocyte activation may play a role in ALS pathogenesis. Therefore, monocyte CCR2, the receptor for monocyte chemoattractant protein-1 (MCP-1), and plasma levels of MCP-1 were measured in 42 sALS patients, 38 healthy and 34 age-related macular degeneration (ARMD) controls. MCP-1 was elevated in both sALS and ARMD patients, but CCR2 levels were significantly decreased on sALS but not on ARMD monocytes. Loss of monocyte CCR2 expression was inversely correlated with degree of monocyte/macrophage activation in sALS and this decrease was unlikely due to receptor down-regulation given the ARMD results. Defective monocyte/macrophages may play an active role in sALS.

Increased plasma monocyte chemoattractant protein‐1 level in idiopathic pulmonary arterial hypertension

Monocyte chemoattractant protein-1 (MCP-1), a pro-inflammatory chemokine, has potent chemoattractant activity for monocytes/macrophages. We sought to investigate the clinical significance of MCP-1 in idiopathic pulmonary arterial hypertension (IPAH). This study included 28 patients with IPAH, seven patients with pulmonary arterial hypertension (PAH) related to collagen vascular disease, and 13 healthy subjects. Plasma MCP-1 levels were measured together with serum IL-6 and tumour necrosis factor-alpha (TNF-alpha) levels. Circulating levels of MCP-1, IL-6 and TNF-alpha were significantly higher in patients with IPAH than in healthy controls, although they were lower than in patients with PAH related to collagen vascular disease. Plasma MCP-1 did not significantly correlate with any haemodynamic variables. However, plasma MCP-1 levels correlated negatively with the disease duration (time from symptom onset). Plasma MCP-1 levels were elevated in patients with IPAH, and this elevation was particularly marked in the early stage of disease. Taking into account the chemoattractant activity of MCP-1, these results imply a contribution of MCP-1 to the development of pulmonary hypertension.

Tetrapeptide AcSDKP Induces Postischemic Neovascularization Through Monocyte Chemoattractant Protein-1 Signaling

We investigated the putative proangiogenic activity and molecular pathway(s) of the tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) in a model of surgically induced hindlimb ischemia. Hindlimb ischemia was induced by femoral artery ligature and an osmotic minipump was implanted subcutaneously to deliver low (0.12 mg/kg per day) or high (1.2 mg/kg per day) doses of AcSDKP, for 7 or 21 days. Angiography scores, arteriole density, capillary number, and foot perfusion were increased at day 21 in the high-dose AcSDKP-treated mice (by 1.9-, 1.8-, 1.3-, and 1.6-fold, respectively) compared with control animals (P<0.05, P<0.01, P<0.01, respectively). AcSDKP treatment for 24 hours upregulated the monocyte chemoattractant protein-1 (MCP-1) mRNA and protein levels by 1.5-fold in cultured endothelial cells (P<0.01). In the ischemic hindlimb model, administration of AcSDKP also enhanced MCP-1 mRNA levels by 90-fold in ischemic leg (P<0.001) and MCP-1 plasma levels by 3-fold (P<0.001 versus untreated ischemic control mice). MCP-1 levels upregulation were associated with a 2.3-fold increase in the number of Mac3-positive cells in ischemic area of AcSDKP-treated mice (P<0.001 versus untreated animals). Interestingly, AcSDKP-induced monocyte/macrophage infiltration and postischemic neovascularization was fully blunted in MCP-1-deficient animals. AcSDKP stimulates postischemic neovascularization through activation of a proinflammatory MCP-1-related pathway.

Altered Vessel Signalling Molecules in Subjects with Down's Syndrome

Downs syndrome (DS) is the most frequent human chromosomal abnormality and is associated with mental retardation. Some evidence indicates that certain inflammatory molecules may be increased in DS. Proinflammatory and vasoactive molecules in the blood of non demented subjects with DS were measured in the present investigation. Plasma levels of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1) and C reactive protein (CRP) were measured in child (2-14 years), adult (20-50 yrs) and elderly (> 60 yrs) DS subjects. Increased plasma levels of IL-6 and MCP-1 were present in DS. Plasma levels of VEGF were increased only in DS adults. Positive linear correlation between IL-6 and MCP-1 levels was present. However, no subclinical inflammation was apparent in DS, since neopterin and CRP levels were within the normal range. An altered regulation of these molecules might interfere with some processes involved in cognitive performances of DS subjects.

Chemokine drives tuberculosis

High levels of the chemokine monocyte chemoattractant protein-1 (MCP-1) give tuberculosis (TB) the upper hand, according to a population study on page 1649. Flores-Villanueva and colleagues show that individuals whose cells are genetically programmed to produce copious amounts of MCP-1 are more likely to develop active disease when infected with Mycobacterium tuberculosis. Figure Tuberculosis patients homozygous for the MCP-1 –2518G allele (GG) have the highest plasma levels of MCP-1. Infections with M. tuberculosis, the causative agent of TB, are on the rise; an estimated eight million new infections and two million TB-induced deaths occur annually. But not all people who are exposed to M. tuberculosis become ill—a phenomenon largely attributed to genetic differences that make some individuals more susceptible to disease than others. Indeed, a recent study identified a region on chromosome 17 that was linked to increased susceptibility to active tuberculosis, although the exact gene(s) responsible for this effect was not identified. Flores-Villanueva and colleagues now show that a polymorphism in the promoter of the MCP-1 gene, which resides on chromosome 17, is the likely culprit of this increased susceptibility. In a group of infected individuals from Mexico, this polymorphism (-2518G) was five times more prevalent in patients with active TB than in those who remained healthy. This polymorphism was previously shown to cause increased expression of the MCP-1 protein. MCP-1 is an attractant for monocytes and T cells, two cell types that help to form the granulomas that contain the bacteria, and is thus thought to help orchestrate the initial response to M. tuberculosis infection. But extremely high levels of MCP-1 can inhibit the expression of interleukin (IL)-12, a cytokine primarily produced by dendritic cells and monocytes that is required to activate antibacterial effector cells. Indeed, monocytes isolated from patients homozygous for the -2518G allele produced high levels of MCP-1 and low levels of IL-12 when stimulated with M. tuberculosis extracts. In an accompanying commentary (page 1617), Alcais and colleagues note that the presence of the -2518G susceptibility allele in approximately half of the Mexican population means that, in the absence of other genetic factors, the attributable risk of this mutation for developing disease could exceed 60%—the largest genetic impact on adult TB ever described.

Contribution of the familial and genetic factors on monocyte chemoattractant protein-1 variation in healthy human pedigrees

Monocyte chemoattractant protein-1 (MCP-1) is a chemokine whose circulating levels have been detected in the lesions of several diseases such as pulmonary fibrosis, rheumatoid arthritis and atherosclerosis. However, the factors involved in the regulation of its production remain largely unknown. The main aim of the present paper was to ascertain the contribution of the familial/genetic factors on the production of MCP-1 in apparently healthy individuals. We also tested the possible relationships between the plasma levels of MCP-1 and other cytokines involved in bone metabolism (receptor activator NF-kB ligand (RANKL), osteoprotegerin (OPG), interleukin-6, macrophage-colony stimulating factor, tumor necrosis factor-α). Using ELISA assays the cytokine levels were measured in 570 apparently healthy individuals belonging to ethnically homogeneous Caucasian families. We found that MCP-1 levels were significantly ( P < 0.01) correlated with RANKL (in both sexes) and with OPG only in women. The study showed that adjusted for potential covariates, 72% of the MCP-1 variance, was attributable to familial effects. About 49% was due to potential genetic factors and the rest was explained by common environmental sources shared by spouses within each family. In conclusion, our data provide reliable evidence for the substantial role of genetic factors in the determination of the phenotypic variability of MCP-1 plasma levels. The association between the osteoclastogenic cytokines and MCP-1 levels in healthy pedigrees is of special interest and might shed light on MCP-1 involvement in bone remodeling.

Parenteral iron treatment induces MCP-1 accumulation in plasma, normal kidneys, and in experimental nephropathy

Monocyte chemoattractant protein-1 (MCP-1) promotes renal inflammation, thereby contributing to acute and chronic nephropathies. Its production is stimulated by oxidative stress. Thus, this study tested whether pro-oxidant iron/carbohydrate complexes, used to treat iron deficiency, induce MCP-1 in renal/extrarenal tissues, in plasma, and in the setting of experimental nephropathy. CD-1 mice received 2 mg of intravenous iron [complexed with dextran (iron dextran), sucrose (iron sucrose), or gluconate (iron gluconate)]. Renal MCP-1 and/or its mRNA were measured 3 hours to 7 days post-iron injection. Iron effects on liver, lung, spleen, and heart MCP-1 mRNA, and on peritoneal lavage fluid MCP-1 concentrations were assessed. Iron pretreatment effects on MCP-1 levels in unilaterally obstructed kidneys vs. contralateral kidneys were determined. Finally, iron gluconate's influence on proximal tubule [human kidney-2 (HK-2)] cell MCP-1 levels was assessed. Iron sucrose (the primary test agent) markedly increased plasma and renal MCP-1 levels. It also induced multiorgan MCP-1 mRNA increments (liver > spleen > kidney > lung > heart). Iron gluconate was more potent than iron sucrose; conversely, iron dextran had no discernible effect. The iron dextran and iron sucrose-induced renal MCP-1 mRNA increments ( approximately 4x) were persistent, lasting for at least 3 to 7 days. Iron gluconate raised MCP-1 levels in peritoneal lavage fluid. It also doubled MCP-1 in unilaterally obstructed kidneys (ureteral ligation) without altering contralateral (control kidney) MCP-1 content. Iron gluconate raised HK-2 cell MCP-1, implying a direct proximal tubule effect. Iron sucrose and iron gluconate (but not iron dextran) can induce MCP-1 generation in renal and extrarenal tissues, possibly via transcriptional events. This may dramatically impact renal disease-induced MCP-1 increments. Finally, iron can increase peritoneal lavage fluid MCP-1 levels. Whether the above changes have implications for renal disease progression, and/or for peritoneal inflammation/peritoneal dialysis efficiency, are issues which may need to be addressed.

Enhanced levels of platelet P-selectin and circulating cytokines in young patients with mild arterial hypertension

Emerging evidence links inflammation to atherosclerosis (AS). Although some studies have addressed the role of inflammation in patients with arterial hypertension (AH), its overall contribution in AH is far from being understood. Therefore, the present pilot study was designed to examine the role of platelet P-selectin and various inflammatory mediators in young patients with moderate AH without signs of target organ damage. Fifteen patients with mild AH [33.8 +/- 7.3 years, mean arterial pressure (MAP) 106.6 +/- 10.4 mmHg] and 15 healthy normotensive controls (31.7 +/- 10.6 years) were examined. Platelet P-selectin was analysed by flow cytometry. Plasma levels of monocyte-chemoattractant-protein-1 (MCP-1), high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, tumour necrosis factor alpha (TNFalpha), and IL-10 levels were measured by enzyme immunoassay (EIA). Patients with mild AH showed significantly enhanced expression of platelet P-selectin [17.2 +/- 5.4 versus 10.6 +/- 4.2 mean fluorescence intensity (MFI), P < 0.001]. P-selectin expression positively correlated with MAP (r = 0.43, P < 0.05). Furthermore, patients with mild AH had significantly enhanced plasma levels of hsCRP (2.7 +/- 3.8 versus 0.6 +/- 0.9 mg/l, P < 0.01), IL-6 (1.4 +/- 0.7 versus 0.6 +/- 0.3 pg/ml, P < 0.001), TNFalpha (2.8 +/- 0.7 versus 2.4 +/- 0.4 pg/ml, P < 0.05), and MCP-1 (291.3 +/- 100.7 versus 214.3 +/- 8.3 pg/ml, P < 0.05). IL-6 levels positively correlated with hsCRP levels (r = 0.47, P < 0.05) and mean arterial pressure (MAP) (r = 0.44, P < 0.05). This pilot study demonstrates that in an early stage of AH, inflammatory pathways are already activated. Besides pro-inflammatory cytokines, platelets seem to play a significant role in mediating inflammation in AH, which could lead to target organ injury. Further investigations have to clarify the role of early anti-inflammatory therapy, in patients with mild to moderate AH, in alleviating hypertensive target organ damage.

Plasma MCP-1 level and risk for peripheral arterial disease and incident coronary heart disease: Atherosclerosis Risk in Communities study

Monocyte chemoattractant protein-1 (MCP-1), which mediates the recruitment of monocytes, has been suggested to play a role in atherosclerosis. Because the correlation between circulating MCP-1 and cardiovascular risk has not been thoroughly investigated, we determined the relationship between MCP-1 level and peripheral arterial disease (PAD) or coronary heart disease (CHD). In the Atherosclerosis Risk in Communities (ARIC) study, 209 cases with lower extremity PAD and 412 cases with incident CHD were compared with 733 and 709 subjects without PAD and CHD, respectively. Mean plasma MCP-1 levels were significantly higher in PAD cases (468.7 versus 416.5 pg/mL in non-cases). MCP-1 levels correlated significantly with other inflammatory markers in comparison subjects. Logistic regression analyses showed a significant association of MCP-1 with PAD, independent of traditional CHD risk factors, with an odds ratio of 2.14 (95% CI, 1.28–3.60) for the highest MCP-1 tertile compared with the lowest. Incident CHD risk increased significantly per 1standard deviation (S.D.) difference in MCP-1 level independent of other cardiovascular risk factors, including inflammatory markers. These data show that MCP-1 is associated with atherosclerotic disease in two vascular beds and suggest that MCP-1 may be a novel target for atherosclerosis therapy.

The PPARδ agonist GW0742X reduces atherosclerosis in LDLR −/− mice

Several lines of evidence suggest a biological role for peroxisome proliferator-activated receptor (PPARδ) in the pathogenesis of atherosclerosis. Administration of synthetic PPARδ agonists to obese rhesus monkeys elevates serum high-density lipoprotein (HDL) cholesterol as a result of increased reverse cholesterol transport whilst in vitro studies have suggested a role for PPARδ in lipid uptake into macrophages. Recent studies have found that PPARδ depletion from macrophages in LDL receptor (LDLR −/−) mice decreases lesion area via modulation of the inflammatory status of the macrophage, an effect also seen on pharmacological activation of PPARδ in vitro. We demonstrate here that the PPARδ agonist, GW0742X has potent anti-atherogenic activity in the LDLR −/− mouse, decreasing lesion area by up to 50%. Administration of GW0742X had no effect on total cholesterol, HDL or LDL cholesterol and modest effects on very low-density lipoprotein (VLDL). Treatment with GW0742X resulted in decreased expression of monocyte chemoattractant protein 1 (MCP-1) and intracellular adhesion moleculae 1 (ICAM-1) in the aortae of treated mice. In addition, GW0742X decreased tumour necrosis factor-alpha (TNFα) expression in peritoneal macrophages, aortae and adipose tissue in comparison with control animals. Changes in gene expression were reflected in decreased plasma levels of MCP-1. These observations support an atheroprotective effect of PPARδ agonists in vivo.

Periodic acceleration enhances release of nitric oxide in healthy adults

Periodic acceleration in the direction of the spinal axis through repetitive movements of a horizontal motion platform increases intravascular pulsatile shear stress. We hypothesized that periodic acceleration enhances release of nitric oxide (NO) in healthy subjects. We enrolled 8 healthy volunteers [39 ± 10 (SD) years]. Periodic acceleration was applied with the motion platform at a frequency of 2–3 Hz with approximately ± 0.25 g for 45 min in the fasting state. The procedure was repeated 20 times over 31 ± 10 days. Venous blood was sampled to determine plasma levels of NO, vascular endothelial growth factor (VEGF), tissue plasminogen activator (t-PA), and monocyte chemoattractant protein-1 (MCP-1) before and immediately after the first and 20th session. All the 8 subjects completed the 20 sessions without any adverse side effect. Periodic acceleration significantly increased the plasma levels of endproducts of NO from 17 ± 3 μmol/L at baseline and immediately after the first session to 24 ± 9 μmol/L immediately after the 20th session (each p < 0.05). Treatment with the motion platform did not change significantly the plasma levels of VEGF, t-PA, and MCP-1. These findings provide new evidence that periodic acceleration with the motion platform enhances release of NO.

Prognostic usefulness of plasma monocyte/macrophage and T-lymphocyte activation markers in patients with acute coronary syndromes

Macrophages and T lymphocytes accumulate and are activated in atherosclerotic plaques. We tested the hypothesis that plasma levels of the monocyte/macrophage and T-lymphocyte activation markers, monocyte chemoattractant protein-1 (MCP-1) and soluble interleukin-2 receptor (sIL-2r), respectively, can be used in acute coronary syndrome classification and risk prediction. Blood samples were collected at hospital admissions of 183 patients who had ischemic chest pain. Of these, 59 had acute myocardial infarction, 60 had unstable angina, and 64 had angina pectoris. No significant differences in the levels or proportions of subjects with increased levels of MCP-1 or sIL-2r were found across groups. During a mean follow-up of 13 months, 117 patients (64%) had a study end point (i.e., cardiac death, recurrent myocardial infarction, unstable angina, or revascularization). Increased levels (above median) of MCP-1 and sIL-2r were associated with increased risk, with odds ratios of 1.85 (95% confidence interval 0.92 to 3.73, p = 0.08) and 2.34 (95% confidence interval 1.16 to 4.71, p <0.02), respectively. In summary, in this unselected patient population with a very high rate of coronary events during follow-up, increased plasma levels of MCP-1 and sIL-2r were helpful for predicting new coronary events.

Association between the A-2518G polymorphism in the monocyte chemoattractant protein-1 gene and insulin resistance and Type 2 diabetes mellitus.

The molecular mechanisms of obesity-related insulin resistance are incompletely understood. Macrophages accumulate in adipose tissue of obese individuals. In obesity, monocyte chemoattractant protein-1 (MCP-1), a key chemokine in the process of macrophage accumulation, is overexpressed in adipose tissue. MCP-1 is an insulin-responsive gene that continues to respond to exogenous insulin in insulin-resistant adipocytes and mice. MCP-1 decreases insulin-stimulated glucose uptake into adipocytes. The A-2518G polymorphism in the distal regulatory region of MCP-1 may regulate gene expression. The aim of this study was to investigate the impact of this gene polymorphism on insulin resistance. We genotyped the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort ( n=3307). Insulin resistance, estimated by homeostasis model assessment, and Type 2 diabetes were diagnosed in 803 and 635 patients respectively. Univariate analysis revealed that plasma MCP-1 levels were significantly and positively correlated with WHR ( p=0.011), insulin resistance ( p=0.0097) and diabetes ( p<0.0001). Presence of the MCP-1 G-2518 allele was associated with decreased plasma MCP-1 ( p=0.017), a decreased prevalence of insulin resistance (odds ratio [OR]=0.82, 95% CI: 0.70-0.97, p=0.021) and a decreased prevalence of diabetes (OR=0.80, 95% CI: 0.67-0.96, p=0.014). In multivariate analysis, the G allele retained statistical significance as a negative predictor of insulin resistance (OR=0.78, 95% CI: 0.65-0.93, p=0.0060) and diabetes (OR=0.80, 95% CI: 0.66-0.96, p=0.018). In a large cohort of Caucasians, the MCP-1 G-2518 gene variant was significantly and negatively correlated with plasma MCP-1 levels and the prevalence of insulin resistance and Type 2 diabetes. These results add to recent evidence supporting a role for MCP-1 in pathologies associated with hyperinsulinaemia.

Oxidative Stress Influences CC-Chemokine Levels in Hemodialyzed Patients

Background: Increased oxidative stress (SOX) has been reported in hemodialyzed (HD) patients, but its influence on CC-chemokine levels remains unknown. Methods: The levels of 3 distinct SOX markers (Cu/Zn superoxide dismutase (Cu/Zn SOD), total lipid peroxide, and autoantibodies against oxidized LDL (OxLDL-Ab)), as well as those of 4 CC-chemokines (monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory proteins (MIP-1α, MIP-1β), regulated upon activation, normal T cell expressed and secreted (RANTES), and tumor necrosis factor-α (TNF-α)) were measured pre- and post-HD session in 15 HD patients with cardiovascular disease (CVD) and 12 HD patients without CVD (pre- and post-HD session) and 17 controls. Results: Cu/Zn SOD levels were elevated in HD patients (both before and after HD) compared to controls (p < 0.001). Total lipid peroxide levels were similar in the controls in pre-dialysis samples, but were increased after a HD session (p < 0.001). Pre-dialysis OxLDL-Ab levels were increased only in the HD group with CVD compared to controls (p < 0.05). The pre-dialysis plasma levels of TNF-α (p < 0.001), MCP-1 (p < 0.001) and MIP-1β (p < 0.01) were increased both in all HD patients and subgroups with CVD when compared to the controls, and remained significantly elevated when measured after HD. Dialysis increased MCP-1 (p < 0.05) and MIP-1β (p < 0.001) levels as compared to the controls as well as in patients without CVD. Plasma RANTES was significantly lower before HD (p < 0.05) and after HD (p < 0.001) in patients with CVD. Patients without CVD and all HD patients also had lower RANTES before and after HD when compared to controls (all p < 0.001). A positive correlation was observed between plasma pre-dialysis Cu/Zn SOD levels and the other SOX markers (all p < 0.05), age (p < 0.05) and duration of hemodialysis (p < 0.001). A positive relationship existed between plasma Cu/Zn SOD levels and those of MCP-1, MIP-1β and TNF-α (all p < 0.001). RANTES levels negatively correlated with Cu/Zn SOD (p < 0.0001).TNF-α positively correlated with age (p < 0.05), total lipid peroxide (p = 0.010), MCP-1 (p < 0.01) and MIP-1β levels (p < 0.01). An identifiable association exists between MCP-1 and MIP-1β levels (p < 0.01), whereas both MCP-1 and MIP-1β were inversely correlated with RANTES (both p < 0.05). Conclusion: Our data indicate for the first time a probable functional relationship between oxidative stress and CC-chemokine levels in hemodialyzed patients, particularly in those with cardiovascular disease. This relationship may represent one of the mechanisms involved in the progression of atherosclerosis in these patients.

Adiposity Elevates Plasma MCP-1 Levels Leading to the Increased CD11b-positive Monocytes in Mice

Obesity is currently considered as an epidemic in the western world, and it represents a major risk factor for life-threatening diseases such as heart attack, stroke, diabetes, and cancer. Taking advantage of DNA microarray technology, we tried to identify the molecules explaining the relationship between obesity and vascular disorders, comparing mRNA expression of about 12,000 genes in white adipose tissue between normal, high fat diet-induced obesity (DIO) and d-Trp34 neuropeptide Y-induced obesity in mice. Expression of monocyte chemoattractant protein-1 (MCP-1) mRNA displayed a 7.2-fold increase in obese mice as compared with normal mice, leading to substantially elevated MCP-1 protein levels in adipocytes. MCP-1 levels in plasma were also increased in DIO mice, and a strong correlation between plasma MCP-1 levels and body weight was identified. We also showed that elevated MCP-1 protein levels in plasma increased the CD11b-positive monocyte/macrophage population in DIO mice. Furthermore, infusion of MCP-1 into lean mice increased the CD11b-positive monocyte population without inducing changes in body weight. Given the importance of MCP-1 in activation of monocytes and subsequent atherosclerotic development, these results suggest a novel role of adiposity in the development of vascular disorders.