Ursolic acid protects diabetic mice against monocyte dysfunction and accelerated atherosclerosis

Aims

Accelerated atherosclerosis is a major diabetic complication initiated by the enhanced recruitment of monocytes into the vasculature. In this study, we examined the therapeutic potential of the phytonutrients ursolic acid (UA) and resveratrol (RES) in preventing monocyte recruitment and accelerated atherosclerosis.

Methods and results

Dietary supplementation with either RES or UA (0.2%) protected against accelerated atherosclerosis induced by streptozotocin in high-fat diet-fed LDL receptor-deficient mice. However, mice that received dietary UA for 11 weeks were significantly better protected and showed a 53% reduction in lesion formation while mice fed a RES-supplemented diet showed only a 31% reduction in lesion size. Importantly, UA was also significantly more effective in preventing the appearance of proinflammatory GR-1^high monocytes induced by these diabetic conditions and reducing monocyte recruitment into MCP-1-loaded Matrigel plugs implanted into these diabetic mice. Oxidatively stressed THP-1 monocytes mimicked the behavior of blood monocytes in diabetic mice and showed enhanced responsiveness to monocyte chemoattractant protein-1 (MCP-1) without changing MCP-1 receptor (CCR2) surface expression. Pretreatment of THP-1 monocytes with RES or UA (0.3–10 μM) for 15 h resulted in the dose-dependent inhibition of H₂O₂-accelerated chemotaxis in response to MCP-1, but with an IC₅₀ of 0.4 μM, UA was 2.7-fold more potent than RES.

Conclusion

Dietary UA is a potent inhibitor of monocyte dysfunction and accelerated atherosclerosis induced by diabetes. These studies identify ursolic acid as a potential therapeutic agent for the treatment of diabetic complications, including accelerated atherosclerosis, and provide a novel mechanism for the anti-atherogenic properties of ursolic acid.     

Association of soluble CD40 ligand with carotid atherosclerosis in Japanese type 1 diabetic patients

Aims/hypothesis It has recently been shown that the soluble form of CD40 ligand (sCD40L) interacts with CD40 on vascular cells, leading to a variety of proinflammatory responses, and that serum sCD40L levels can be a predictive marker of cardiovascular events. The aim of this study was to estimate sCD40L levels in type 1 diabetic patients to examine a possible association with carotid atherosclerosis.Subjects and methods Human sCD40L levels in serum and intima–media thickness (IMT) of carotid artery were examined in 80 Japanese type 1 diabetic patients (27 men and 53 women, age 22.8±3.4 years (mean±SD), duration of diabetes 13.2±6.1 years) and 20 healthy age-matched non-diabetic individuals.Results Serum sCD40L levels were significantly (p=0.0185) higher in subjects with type 1 diabetes (2.10±1.33 ng/ml) compared with non-diabetic subjects (1.35±0.88 ng/ml). The greatest IMT (Max-IMT) and averaged IMT (Mean-IMT) were also significantly greater in patients with type 1 diabetes than in control subjects (0.73±0.14 vs 0.64±0.07 mm, p=0.0041, 0.63±0.09 vs 0.57±0.06 mm, p=0.0066, respectively). Levels of sCD40L were statistically significantly associated with Max-IMT (r=0.383, p<0.001) and Mean-IMT (r=0.275, p=0.0058). Furthermore, stepwise multivariate regression analyses demonstrated that sCD40L is a determinant of both Max- and Mean-IMT, independently of conventional risk factors.Conclusions/interpretation It is suggested that increased levels of serum sCD40L are associated with accelerated atherosclerotic change observed in young patients with type 1 diabetes.     

Intravenous Cocaine Results in an Acute Decrease in Levels of Biomarkers of Vascular Inflammation in Humans

Cocaine use causes significant cardiovascular morbidity from its hemodynamic effects. It is less clear whether cocaine promotes atherosclerosis. Vascular inflammation is one of the earliest steps in the pathophysiology of atherosclerosis. We hypothesized that cocaine results in an increase in inflammatory markers. Study objective was to measure the acute effects of intravenous cocaine on biomarkers of vascular inflammation. Eleven chronic cocaine users were enrolled. After a drug-free period, they received intravenous cocaine at 0.36 mg/kg dose in an in-hospital controlled environment. Serum levels of soluble CD40 ligand, monocyte chemoattractant protein-1, interleukin 6, and soluble intercellular adhesion molecule-1 were measured at baseline, 6 h, 24 h, and 6 days after cocaine challenge and at baseline for controls. After cocaine challenge, sCD40 ligand levels decreased in subjects and were significantly lower at 24 h. MCP-1 levels decreased and were significantly lower at the 6-day time point. No significant changes in IL-6 or sICAM-1 level were found. In conclusion, intravenous cocaine did not result in an increase in levels of inflammatory markers. Levels of MCP-1 and sCD40L decreased significantly. This unexpected finding suggests that chronic effects of cocaine on inflammation may be different from acute effects or that higher dosing may have differential effects as compared to lower dose used here.     

Circulating intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in patients with type 2 diabetes mellitus

Serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin in patients with type 2 diabetes mellitus (n = 64) and control subjects (n = 40) were studied. Serum ICAM-1 concentrations in diabetic patients were significantly higher than those of control subjects (378.2 +/- 70.0 versus 220.4 +/- 31.8 ng/ml, P < 0.01). By multiple regression analysis, hemoglobin A1c was independently associated with serum ICAM-1 concentration in patients with diabetes. The serum VCAM-1 concentration of diabetic patients with macroangiopathy was higher than those of patients without macroangiopathy and of control subjects (806.9 + 276.5 versus 639.0 +/- 146.0 (P < 0.01), and 652.1 +/- 146.9 ng/ml (P < 0.01), respectively). There was no difference in serum E-selectin concentration between diabetic patients with or without macroangiopathy and normal control subjects. These results suggest that adhesion molecules may contribute to the development of atherosclerosis in the diabetic state.     

The effect of cigarette smoking on soluble adhesion molecules in middle-aged patients with Type 2 diabetes mellitus.

AIMS: To investigate the effect of smoking on soluble adhesion molecules in middle-aged diabetic patients. METHODS: One hundred out-patients with Type 2 diabetes and 100 age- and sex-matched non-diabetic subjects without clinical macrovascular disease were selected. Soluble serum levels of adhesion molecules were analysed using enzyme immunoassay. Carotid atherosclerosis was assessed using an ultrasound system. RESULTS: When compared with non-diabetic subjects, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), and sE-selectin were found at significantly high levels in diabetic patients and significantly higher levels of sICAM-1, sE-selectin, and sP-selectin were observed in current smokers than never-smokers among diabetic or non-diabetic subjects, respectively. The combined, but not enhanced, effects of diabetes mellitus and smoking were observed in sICAM-1 and sE-selectin levels. Additionally, levels of sICAM-1 (P < 0.05) and sE-selectin (P < 0.01), but not sP-selectin, were high in ex-smokers when compared with never-smokers among diabetic patients. Diabetic smokers were also found to have marked carotid atherosclerosis, which was related to increased levels of sICAM-1. CONCLUSIONS: Our present study shows that levels of adhesion molecules were higher in diabetic smokers than diabetic non-smokers or non-diabetic smokers, and that cessation after chronic smoking did not restore the levels of sICAM-1 and sE-selectin, though sP-selectin levels were restored. These data suggest a possible mechanism for accelerated atherosclerosis induced by smoking in patients with diabetes.     

Benefits of gliclazide in the atherosclerotic process: decrease in monocyte adhesion to endothelial cells

Atherosclerotic cardiovascular disease is the leading cause of premature death in patients with diabetes. Atherosclerosis is a chronic immune-mediated disease, the initiation, progression, and destabilization of which is driven and regulated by inflammatory cells. One critical event in the initiation of this vascular inflammatory disease is the adhesion of leukocytes to the activated endothelium and their migration into the vessel wall. These processes are mediated by the upregulation of adhesion molecules on endothelial cells (ECs) and an increased expression in the vascular wall of chemotactic factors to leukocytes. Monocyte binding to ECs is increased in diabetes. One major determinant of this alteration could be oxidative stress. Given the free-radical scavenging activity of gliclazide, we determined the ex vivo and in vitro effects of this drug on human monocyte binding to ECs and the molecular mechanisms involved in this effect. Our results demonstrate that short-term administration of gliclazide to patients with type 2 diabetes normalizes the levels of plasma lipid peroxides and monocyte adhesion in these subjects. Gliclazide (10 μg/mL) also reduces oxidized low-density lipoprotein (oxLDL)- and advanced glycation end product (AGE)-induced monocyte adhesion to ECs in vitro. The inhibitory effect of this drug on AGE-induced monocyte adhesion involves a reduction in EC adhesion molecule expression and inhibition of nuclear factor κB (NF-κB) activation. In addition, gliclazide inhibits oxLDL-induced monocyte adhesion to cultured human aortic vascular smooth muscle cells (HASMCs) in vitro and reduces the production of monocyte chemotactic protein-1 (MCP-1) by these cells. Taken collectively, these results show that gliclazide, at concentrations in the therapeutic range, inhibits ex vivo and in vitro monocyte adhesiveness to vascular cells. By doing so, this drug could reduce monocyte recruitment into the vessel wall and thereby contribute to attenuating the sustained inflammatory process that occurs in the atherosclerotic plaque. These findings suggest that treatment of diabetic patients with this drug may prevent or retard the development of vasculopathies associated with diabetes.     

Low-grade inflammation, endothelial activation and carotid intima-media thickness in type 2 diabetes

OBJECTIVES: The objective of this study was to assess the relationship between inflammation, endothelial activation and incipient atherosclerosis in type 2 diabetes. DESIGN: Cross-sectional study. Setting and subjects. We studied 239 type 2 diabetic patients [71 with clinical cardiovascular disease (CVD)] and 78 healthy control subjects, aged 50-75 in a single research centre. METHODS: Carotid intima-media thickness (IMT) was determined by ultrasound. Circulating intracellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, ultra-sensitive C-reactive protein, human serum amyloid A, interleukin-6, monocyte colony-stimulating factor, secretory nonpancreatic phospholipase A(2) type IIA, glucose, HbA1c, and lipid/lipoprotein variables were measured. RESULTS: Carotid IMT was significantly thicker in diabetic patients than healthy controls across the whole age range. IMT was also thicker in diabetic patients with, than without, CVD, but this difference disappeared after controlling for confounding factors. Concentrations of the inflammatory and endothelial markers except IL-6 were significantly higher in the diabetic patients than in healthy controls, but comparable in diabetic patients with and without CVD. The main determinants of IMT in the diabetic patients were blood pressure, age and diabetes duration. CONCLUSIONS: Low-grade inflammation and endothelial activation are increased in diabetic patients but do not associate with IMT or clinical CVD. The inflammatory reaction seems to be rather a feature of the metabolic syndrome than a direct determinant of atherosclerosis.     

The effect of simvastatin on the serum monocyte chemoattractant protein-1 and intracellular adhesion molecule-1 levels in diabetic rats

ObjectiveThis study aimed to observe the effect of simvastatin on the serum monocyte chemoattractant protein-1 (MCP-1) and intracellular adhesion molecule-1 (ICAM-1) levels and to probe its protective mechanisms on macroangiopathy in diabetic rats.MethodsTwenty-four Wistar rats were randomly assigned to a normal control group (Group A, n=8), and STZ-induced diabetic group (Group B, n=8), or a simvastatin-treated diabetic group (Group C, n=8). Rats in Group C were treated with simvastatin (20 mg kg^?1 day^?1) 1 week after the establishment of the diabetic model. Groups A and B were treated with corresponding sodium chloride. Peripheral blood glucose was tested weekly; serum MCP-1, ICAM-1, and HbA1c levels were tested at the eighth week.ResultsAt the second, fourth, and eighth week, peripheral blood glucose levels in Group B were similar to those of Group C, which were much higher than those of Group A. Serum MCP-1 and ICAM-1 levels in Groups B and C were higher than those of Group A (P<.01), and serum MCP-1 and ICAM-1 levels in Group C were lower than those of Group B (P<.01); HbA1c was not significantly different between Group C and Group B.ConclusionSimvastatin has the effect of anti-inflammation, which may play some protection against the progress of atherosclerosis in diabetic rats.     

Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes

Aims/hypothesis

The small, highly conserved vasoactive peptide urotensin II (UII) is upregulated in atherosclerosis. However, its effects in diabetes-associated atherosclerosis have not been assessed.

Methods

Endothelial cells were grown in normal- and high-glucose (5 and 25 mmol/l) media with and without UII (10^?8?mol/l) and/or the UII receptor antagonist, SB-657510 (10^?8?mol/l). Apoe knockout (KO) mice with or without streptozotocin-induced diabetes were treated with or without SB-657510 (30 mg?kg^?1?day^?1; n?=?20 per group) and followed for 20 weeks. Carotid endarterectomy specimens from diabetic and non-diabetic humans were also evaluated.

Results

In high (but not normal) glucose medium, UII significantly increased CCL2 (encodes macrophage chemoattractant protein 1 [MCP-1]) gene expression (human aortic endothelial cells) and increased monocyte adhesion (HUVECs). UII receptor antagonism in diabetic Apoe KO mice significantly attenuated diabetes-associated atherosclerosis and aortic staining for MCP-1, F4/80 (macrophage marker), cyclooxygenase-2, nitrotyrosine and UII. UII staining was significantly increased in carotid endarterectomies from diabetic compared with non-diabetic individuals, as was staining for MCP-1.

Conclusions/interpretation

This is the first report to demonstrate that UII is increased in diabetes-associated atherosclerosis in humans and rodents. Diabetes-associated plaque development was attenuated by UII receptor antagonism in the experimental setting. Thus UII may represent a novel therapeutic target in the treatment of diabetes-associated atherosclerosis.     

Role of Ca(2+)influx in tissue factor expression in monocyte adhesion to endothelial cells

Tissue factor (TF) is the primary initiator of the coagulation cascade. Ca(2+) signaling is involved in TF gene expression. Monocyte chemoattractant protein-1 (MCP-1) and its receptor (CCR2) play a pivotal role in the inflammation of atherosclerosis. Although nitric oxide (NO) impairment appears to promote thrombogenicity in monocyte adhesion to endothelial cells (ECs), little is known about its mechanism. N(omega)-nitro-L-arginine methyl ester (L-NAME) promoted MCP-1 expression in EC culture. In response to monocyte adhesion, increased TF expression accompanied by NF-kappaB p65 activation was observed in L-NAME-treated ECs compared with non-treated ECs. This increased TF expression was prevented by BAPTA-AM, an intracellular Ca(2+) chelator. Monocyte attachment to L-NAME- treated ECs increased Ca(2+) influx compared with non-treated ECs, which was prevented by the blockade of MCP1/CCR2. These findings suggest that increased production of MCP-1 caused by L-NAME contributes to the enhancement of Ca(2+) influx only when monocytes adhered to ECs and that this may accelerate TF expression in ECs triggered by monocyte adhesion. We demonstrate the role of Ca(2+) influx via MCP-1/CCR2 under NO impairment in TF expression in monocyte-EC interaction.     

不同炎性标志物对冠状动脉病变的预测价值

目的 探讨可溶性CD40L、单核细胞趋化蛋白1、白细胞介素8和白细胞介素6等炎性标志物对冠状动脉病变严重程度和稳定性的预测价值.方法 应用流式细胞术检测129例冠心病患者血浆可溶性CD40L、单核细胞趋化蛋白1、白细胞介素8和白细胞介素6水平,计算各类型冠心病患者冠状动脉病变的Gensini积分,分析上述炎性标志物与Gensini积分的相关关系以及对急性冠状动脉综合征的预测价值.结果 四种炎性标志物血浆浓度在冠心病组均显著高于对照组(P均<0.01),其中可溶性CD40L、单核细胞趋化蛋白1和白细胞介素6的浓度在急性心肌梗死组高于稳定型心绞痛组(P=0.001、P=0.009和P=0.011).血浆单核细胞趋化蛋白1和白细胞介素6水平与冠状动脉Gensini积分呈正相关关系(r=0.322, P<0.00001;r=0.203,P=0.026);多因素Logistic回归分析显示白细胞介素6对急性冠状动脉综合征有预测价值(OR=1.275,P=0.037).结论 血浆可溶性CD40L、单核细胞趋化蛋白1、白细胞介素8和白细胞介素6等炎性标志物与冠状动脉粥样硬化病变有关;血浆单核细胞趋化蛋白1和白细胞介素6能反映冠状动脉病变的严重程度;白细胞介素6对预测冠状动脉病变不稳定的冠心病急性冠状动脉综合征有一定价值.     

Lipoxygenase products increase monocyte adhesion to human aortic endothelial cells

The development of atherosclerosis is accelerated in individuals with type 2 diabetes. Adhesion of monocytes to the vascular endothelium is a key initial step in atherogenesis. We have previously shown that monocyte adhesion to human aortic endothelial cells (HAECs) cultured long-term in high-glucose medium (25 mmol/L, 2 passages) is increased compared with cells grown in normal glucose (5 mmol/L). One potential mechanism for increased monocyte adhesion to HAECs under hyperglycemic conditions is via the 12-lipoxygenase (12-LO) pathway. In this study, we demonstrated in HAECs that the major LO metabolite of arachidonic acid was the 12-LO product, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], which was increased severalfold in HAECs cultured under high-glucose conditions. Furthermore, treatment of HAECs with 12(S)-HETE induced monocyte, but not neutrophil, adhesion an average of 3-fold (range of 1.5- to 5-fold) compared with untreated cells (75+/-5 versus 26+/-1 monocytes per field, respectively, P<0.001). Expression of the adhesion molecules vascular cell adhesion molecule-1, E-selectin, and intercellular adhesion molecule-1 was not significantly increased. However, both glucose and 12(S)-HETE induced a 60% increase in HAEC surface expression of connecting segment-1 (ie, CS-1) fibronectin, a ligand for very late-acting antigen-4 (VLA-4). The antibodies used to block monocyte integrin VLA-4 and leukocyte function-related antigen-1, a monocytic counterreceptor for intercellular adhesion molecule-1, inhibited the ability of both 12-LO products and high glucose to induce monocyte adhesion. These results definitively demonstrate for the first time in HAECs that the 12-LO pathway can induce monocyte-endothelial cell interaction and that the effects of glucose may be mediated, at least in part, through this pathway. Thus, these results suggest that the 12-LO pathway may play a role in the increased susceptibility of diabetics to atherosclerosis.     

Circulating advanced glycation end products (AGEs) and soluble form of receptor for AGEs (sRAGE) are independent determinants of serum monocyte chemoattractant protein-1 (MCP-1) levels in patients with type 2 diabetes

BACKGROUND: Atherosclerosis is an inflammatory disease. Monocyte chemoattractant protein-1 (MCP-1) is an essential chemokine responsible for the recruitment of monocytes to inflammatory lesions in the vasculature, an initial step of atherosclerosis. Since serum levels of MCP-1 are higher in patients with type 2 diabetes, inhibition of MCP-1 may be a novel therapeutic target for prevention of accelerated atherosclerosis in diabetes. However, little is known about the regulation and determinants of serum MCP-1 levels in patients with diabetes. In this study, we examined the determinants of serum MCP-1 levels in type 2 diabetic patients. METHODS: Eighty-six consecutive outpatients with type 2 diabetes (36 male and 50 female; mean age 68.4+/-9.6) underwent a complete history and physical examination, determination of blood chemistries, MCP-1, tumour necrosis factor-alpha, adiponectin, advanced glycation end products (AGEs), and soluble form of receptor for AGEs (sRAGE). We examined the association between MCP-1 levels and those in anthropometric, metabolic and inflammatory variables in these subjects. RESULTS: Univariate regression analysis showed that serum levels of MCP-1 were positively associated with AGEs (r=0.386, p<0.001) and sRAGE (r=0.315, p<0.001). After adjusting for age and sex, AGEs (p<0.001) and sRAGE (p<0.05) still remained significant. CONCLUSION: The results demonstrate for the first time that circulating levels of AGEs and sRAGE are independent determinants of serum MCP-1 levels in patients with type 2 diabetes. Our present observations suggest the AGEs-RAGE system may be mainly involved in the elevation of MCP-1 in type 2 diabetic patients.     

2型糖尿病大血管病变与白细胞表面分化抗原40配体、细胞间黏附分子1的相关性研究

探讨白细胞表面分化抗原40配体（CD40L）、细胞间黏附分子1（ICAM-1）与T2DM大血管病变的关系。采用ELISA检测31例健康人（NC组）、47例T2DM患者（DM组）和51例T2DM并大血管病变患者（DM＋MAP组）血浆CD40L、ICAM-1。三组CD40L和ICAM-1均依次增高,组间差异有统计学意义,且血浆CD40L与ICAM-1呈正相关。提示血浆CD40L、ICAM-1表达的增加与T2DM患者大血管病变的发生有关。     

Coronary artery disease progression is associated with C-reactive protein and conventional risk factors but not soluble CD40 ligand

BACKGROUND: Coronary artery disease (CAD) is a major cause of death worldwide. Epidemiological studies have documented conventional risk factors; however, no studies to date have addressed the roles of soluble CD40 ligand (sCD40L) and monocyte chemoattractant protein-1 (MCP-1), and there have been few reports on other novel risk factors in CAD progression. The aim of the present study was to explore the roles of novel and conventional risk factors in CAD progression. METHODS: Patients with stable angina pectoris who underwent repeat coronary angiograms and had serum samples at the time of their first catheterization between March 1999 and January 2004 were enrolled. Those who had progression of coronary atherosclerosis were classified into the progression group (n = 66). Those who did not have CAD progression were classified into the nonprogression group (n = 124). RESULTS: There were more cases of diabetes mellitus (36% versus 20%; P = 0.024) and more men (92% versus 81%; P = 0.040) in the CAD progression group than in the nonprogression group, respectively. The progression group also had poorer lipid profiles than the nonprogression group, including higher total cholesterol (188+/-42 mg/dL versus 173+/-39 mg/dL, respectively; P = 0.014) and low density lipoprotein cholesterol (122+/-38 mg/dL versus 112+/-36 mg/dL, respectively; P = 0.025). In terms of inflammatory markers, progression patients had higher baseline high-sensitivity C-reactive protein (hs-CRP) concentrations (P = 0.018), which was also related to the subsequent angiographic severity score changes; however, sCD40L (6182+/-4352 pg/mL versus 6244+/-4602 pg/mL; P = 0.961), MCP-1 (427+/-540 pg/mL versus 341+/-128 pg/mL; P = 0.580) and adhesion molecules concentrations were indifferent between the progression group and the nonprogression group, respectively. Using a multivariate logistical regression model, the ORs for predicting progression were 2.19 for diabetes mellitus, 2.04 for hypercholesterolemia and 1.52 for hs-CRP (P < 0.05). CONCLUSION: In the present study, only conventional risk factors, and particularly hs-CRP, were markers for predicting CAD progression. Novel risk factors, such as concentrations of sCD40L, MCP-1 and adhesion molecules, did not play significant roles.     

Activated platelet and oxidized LDL induce endothelial membrane vesiculation: clinical significance of endothelial cell-derived microparticles in patients with type 2 diabetes.

Endothelial cells, platelets, and oxidized LDL could play very important roles in the development of atherosclerosis in diabetes patients. The levels of plasma endothelial cell-derived microparticles (EDMP), platelet-derived microparticles (PDMP), platelet-P-selectin (plt-PS), soluble CD40 ligand (sCD40L), and anti-oxidized LDL antibody were measured and compared to develop a better understanding of their potential contribution to diabetic vascular complications. The concentrations of EDMP, PDMP, plt-PS, and sCD40L in diabetic patients were significantly higher than those in normal subjects. The number of EDMPs in patients with diabetes complicated by nephropathy was significantly higher than that in those without complications. Levels of anti-oxidized LDL antibody were also higher in type 2 diabetic patients than in control subjects. In addition, anti-oxidized LDL antibody levels correlated with EDMP, PDMP, plt-PS, and sCD40L levels in nephropathy patients. In the nephropathy group treated with sarpogrelate hydrochrolide, a 5-HT(2A) receptor antagonist, EDMP, PDMP, plt-PS, and sCD40L levels were decreased significantly. Oxidized LDL increased expression of plt-PS, and also promoted shedding of PDMP. Furthermore, oxidized LDL promoted a dose-dependent release of 5-hydroxytriptamine. On the other hand, activated platelets and PDMP promoted endothelial cells and THP-1 (monocytic cell line) interaction, and membrane vesiculation occurred in the presence of oxidized LDL. These findings suggest that activated platelets and oxidized LDL induce EDMP generation, and that elevated EDMPs may be a sign of vascular complications in type 2 diabetic patients, particularly those who suffer from diabetes-associated nephropathy.     

Significance of chemokines and soluble CD40 ligand in patients with autoimmune thrombocytopenic purpura

We investigated the levels of various chemokines and soluble CD40L (sCD40L) in ITP patients, in order to determine the influence of CD40-CD40L interaction on the pathogenesis of ITP. We found increases in MCP-1 and RANTES levels in ITP patients compared with those in healthy individuals. Thirty-eight of the 65 ITP patients (58.5%) had elevated levels of sCD40L. We found significant decreases in platelet counts in sCD40L-positive ITP patients. Although the sCD40L level did not differ significantly between the control and nonimmune thrombocytopenia groups, but among ITP patients. sCD40L level was significantly higher in those with untreated ITP than in those with treated ITP. In addition, significant increases in RANTES, MCP-1, sCD14, and sP-selectin levels were observed in sCD40L-positive ITP patients, although sE-selectin levels were not increased in such patients. For other factors examined, however, there were no differences in level between sCD40L-positive and -negative ITP patients. These findings suggests that there are two groups of ITP patients, one with elevated and one with normal of sCD40L. ITP cases in which sCD40L was increased appeared to involve changes in platelet counts and monocyte activation. The pathogenesis of ITP may in some patients include alterations of the CD40/CD40L pathway.     

Effect of statins on soluble CD40 ligand in hypercholesterolemic Type 2 diabetic patients

Hypercholesterolemia and Type 2 diabetes are well-recognized risk factors for cardiovascular disease, promoted by a condition of subclinical inflammation and a hypercoagulable state. Soluble CD40 ligand (sCD40L), a marker of vascular inflammation, seems to predict vascular damage in patients with Type 2 diabetes. Beside the lipid-lowering effect, statins seem to slow the progression of atherosclerosis through a series of anti-inflammatory effects, including a reduction of sCD40L levels. This study compared the effect of a short-term (12 weeks) treatment with rosuvastatin or simvastatin on some markers of inflammation in 36 patients with Type 2 diabetes and moderate hypercholesterolemia. As expected, both drugs significantly modified lipid profile; moreover, rosuvastatin and simvastatin were both able to significantly reduce albumin excretion rate in these patients, without affecting urinary N-acetyl-beta-D-glucosaminidase. Serum homocysteine was not influenced by the treatment, as interleukin-6 levels, while C reactive protein diminished; moreover, rosuvastatin, but not simvastatin, was able to significantly reduce sCD40L. The only clinical parameter related with the variations in sCD40L was systolic blood pressure. In hypercholesterolemic Type 2 diabetic patients, sCD40L, a factor playing a pivotal role in the pathogenesis of atherosclerosis and associated with more rupture-prone lesions, is reduced by short-term treatment with rosuvastatin.     

Platelet and monocyte activity markers and mediators of inflammation in Takotsubo cardiomyopathy

Patients with Takotsubo cardiomyopathy (TC) often present with symptoms similar to those of myocardial infarction (MI). We analyzed blood concentrations of mediators of inflammation and platelet- and monocyte-activity markers in patients with TC and MI for significant differences. Clinical data of patients with TC (n = 16) and acute MI (n = 16) were obtained. Serial blood samples were taken at the time of hospital admission (t ₀), after 2–4 days (t ₁) and after 4–7 weeks (t ₂), respectively. Plasma concentrations of interleukin (IL)-6, IL-7, soluble CD40 ligand (sCD40L), and monocyte chemotactic protein 1 (MCP-1) were determined with an ELISA. Tissue factor binding on monocytes, platelet-activation marker CD62P, platelet CD40-ligand (CD40L), and platelet-monocyte aggregates were measured using flow cytometry. Expression of CD62P on platelets and IL-6 plasma levels were significantly lower in patients with TC compared to MI at the time of hospital admission. IL-7 plasma levels were significantly elevated in patients with TC compared to patients with MI at 2–4 days after hospital admission. No significant differences were observed concerning sCD40L and MCP-1 plasma levels, tissue factor binding on monocytes, CD40L expression on platelets, and platelet-monocyte aggregates at any point in time. Our results indicate that inflammatory mediators and platelet-activity markers contribute to the differences in the pathogenesis of MI and TC.