Plasma Vascular Cell Adhesion Molecule Research Articles

Consumption of the cell-free or heat-treated fractions of a pitched kefir confers some but not all positive impacts of the corresponding whole kefir.

Kefir consumption can have many metabolic health benefits, including, in the case of specific kefirs, improvements in plasma and liver lipid profiles. Our group has previously shown that these health benefits are dependent on the microbial composition of the kefir fermentation, and that a pitched kefir (PK1) containing specific traditional microbes can recapitulate the health benefits of a traditional kefir. In this study we investigated how different preparations of kefir impact cholesterol and lipid metabolism and circulating markers of cardiovascular disease risk and determine if freeze-drying impacts health benefits relative to past studies. Eight-week-old male and female C57Bl/6 mice were fed a high fat diet (40% kcal from fat) supplemented with one of 3 freeze-dried kefir preparations (whole kefir, cell-free kefir, or heat-treated kefir) for 8 weeks prior to analysis of plasma and liver lipid profiles, circulating cardiovascular disease (CVD) biomarkers, cecal microbiome composition, and cecal short-chain fatty acid levels. These groups of mice were compared to others that were fed a control low-fat diet, control high fat diet or high fat diet supplemented with milk, respectively. All kefir preparations lowered plasma cholesterol in both male and female mice, while only whole kefir lowered liver cholesterol and triglycerides. Plasma vascular cell adhesion molecule 1 (VCAM-1) was lowered by both whole kefir and heat-treated kefir in male mice but not females, while c-reactive protein (CRP) was unchanged across all high fat diet fed groups in males and females. These results indicate that some of the metabolic benefits of consumption of this kefir do not require whole kefir while also indicating that there are multiple compounds or components responsible for the different benefits observed.

Type 2 diabetes aggravates Alzheimer's disease-associated vascular alterations of the aorta in mice.

Vascular risk factors are associated with a higher incidence of dementia. In fact, diabetes mellitus is considered a main risk factor for Alzheimer's disease (AD) and both diseases are characterized by vascular dysfunction. However, the underlying mechanisms remain largely unknown. Here, the effects of high-sucrose-induced type 2 diabetes (T2D) in the aorta of wild type (WT) and triple-transgenic AD (3xTg-AD) mice were investigated. 3xTg-AD mice showed a significant decrease in body weight and an increase in postprandial glycemia, glycated hemoglobin (HbA1c), and vascular nitrotyrosine, superoxide anion (O2•-), receptor for the advanced glycation end products (RAGE) protein, and monocyte chemoattractant protein-1 (MCP-1) levels when compared to WT mice. High-sucrose intake caused a significant increase in body weight, postprandial glycemia, HbA1c, triglycerides, plasma vascular cell adhesion molecule 1 (VCAM-1), and vascular nitrotyrosine, O2•-, RAGE, and MCP-1 levels in both WT and 3xTg-AD mice when compared to the respective control group. Also, a significant decrease in nitric oxide-dependent vasorelaxation was observed in 3xTg-AD and sucrose-treated WT mice. In conclusion, AD and T2D promote similar vascular dysfunction of the aorta, this effect being associated with elevated oxidative and nitrosative stress and inflammation. Also, AD-associated vascular alterations are potentiated by T2D. These findings support the idea that metabolic alterations predispose to the onset and progression of dementia.

Natalizumab Blocks VLA-4 Mediated Red Blood Cell Adhesion and Is a Potential Therapy for Sickle Cell Disease

Sickle cell disease (SCD) is caused by a point mutation in the beta-chain of hemoglobin, which triggers a complex pathophysiology resulting in recurrent, painful vaso-occlusive events (VOCs) and chronic hemolytic anemia. Among other abnormalities, sickle red blood cells (RBCs) are more adhesive than normal RBCs. Sickle RBC adhesion is an important pathway leading to both VOC and hemolysis: adhesive interactions promote the formation of blood flow-obstructing heterocellular aggregates that induce ischemic tissue damage and slow the transit of RBCs through the vasculature, promoting sickle hemoglobin polymerization and hemolysis. The capacity of sickle RBCs to adhere to endothelium positively correlates with disease severity. Interventions that reduce sickle RBC adhesion, in particular that of reticulocytes, by blocking specific molecular targets may limit or prevent disease sequelae. Very Late Antigen – 4 (VLA-4 or α4β1 integrin) is an important integrin on reticulocytes that mediates adhesive interactions to endothelial and plasma vascular cell adhesion molecule - 1 (VCAM-1), plasma fibrinogen, and other ligands. VLA-4 is expressed on the surface of sickle reticulocytes, with levels decreasing during maturation such that mature RBCs do not express surface VLA-4. Natalizumab is a recombinant humanized antibody that binds to the α4 subunit of VLA-4 and is used to treat multiple sclerosis (MS) and Crohn’s Disease (CD) by preventing leukocyte trafficking into tissues at sites of inflammation. We investigated the ability of natalizumab to block VLA-4 in the context of sickle whole blood, and evaluated the effect on sickle reticulocyte, mature erythrocyte, and leukocyte adhesion during physiologic flow conditions. Whole blood samples obtained from SCD donors were analyzed for saturation binding of natalizumab to surface VLA-4 on leukocytes and reticulocytes using flow cytometry. Up to 20% of reticulocytes from SCD donors (n=13) were positive for VLA-4 surface staining, whereas VLA-4 was undetectable on the surface of reticulocytes from healthy donors (n=4). VLA-4 on SCD reticulocytes and mononuclear leukocytes was saturated by natalizumab concentrations lower than known plasma trough concentrations achieved in MS and CD patients after natalizumab treatment, with SCD reticulocyte EC50 = 0.11 ± 0.01 μg/mL and SCD leukocyte EC50 = 0.16 ± 0.01 μg/mL (n=6). This translates to a binding affinity of 0.7 to 1.3 nM, similar to that found for healthy donor leukocytes. Both whole blood cells and isolated leukocytes from SCD donors adhered to immobilized VCAM-1 during physiologic flow conditions simulating post-capillary venules (shear stress =1 dynes/cm2) using a microfluidic flow-based adhesion system. Leukocytes from SCD donors adhered more to VCAM-1 (Mean = 20.7 + 10.0 from n=7) than leukocytes from healthy donors (Mean = 5.0 + 1.4 from n=5). The adhesion of leukocytes and reticulocytes to VCAM-1 was blocked by natalizumab in a dose-dependent manner and as a function of natalizumab saturation of cell surface VLA-4. Therapeutic IgG4 antibodies, including natalizumab, undergo chain shuffling in vivo with endogenous IgG4, leading to mono-specific IgG4 molecules, with one Fab arm specific to the antigen it was raised against. Compared to divalent natalizumab, monovalent chain-shuffled natalizumab bound to SCD reticulocytes at a7-fold higher EC50 and inhibited SCD reticulocyte adhesion to VCAM-1 at higher antibody concentrations (10 and 1 µg/mL). While increased, these values are still below trough natalizumab levels achieved in natalizumab-treated patients. In summary, natalizumab bound VLA-4 on the surface of SCD reticulocytes and leukocytes similarly to healthy donor leukocytes and blocked adhesion of SCD reticulocytes and leukocytes to immobilized VCAM-1 under shear conditions. Natalizumab binding and adhesion inhibition occurred at plasma concentrations similar to those seen in natalizumab treated MS and CD patients. Based on these findings, natalizumab may have potential as an anti-adhesive therapy for SCD. Further clinical studies are needed to evaluate the safety and efficacy of natalizumab in SCD. DisclosuresHines:Biogen Idec: Research Funding. Krishnamoorthy:Biogen Idec: Employment, Equity Ownership. White:Biogen Idec: Research Funding. Gupta:Biogen Idec: Employment, Equity Ownership. van der Flier:Biogen Idec: Employment, Equity Ownership. Peters:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment, Equity Ownership. Hobbs:Biogen Idec: Employment, Equity Ownership. Light:Biogen Idec: Employment, Equity Ownership.

Increased leg blood flow and improved femoral artery shear patterns in metabolic syndrome after a diet and exercise programme

Altered vascular shear profiles may contribute to the development of atherosclerosis. Physical activity promotes anti-atherogenic shear patterns, resulting in reduced cardiovascular disease risk. Adults with metabolic syndrome (MetSyn) are at increased risk of developing atherosclerosis and cardiovascular disease. Thus, we hypothesized that conduit artery antegrade shear rate (ASR) would increase and retrograde shear rate (RSR) and oscillatory shear indices (OSI) would decrease in MetSyn patients (n = 16, 51 ± 2 years) after participation in a diet and exercise programme (DEP). Blood flow (Doppler ultrasound, brachial and femoral arteries) was measured, and shear rates were calculated in MetSyn patients before and after 12 weeks of DEP participation. In addition, plasma samples were collected to measure atherogenic markers. Diet and exercise programme participation increased resting leg blood flow and femoral artery ASR (P ≤ 0·05), and tended to decrease OSI (P = 0·09); RSR did not change (P>0·05). No changes in resting arm blood flow or ASR were observed (P>0·05), and both RSR and OSI increased after participation (P≤0·05). DEP participation reduced plasma vascular cell adhesion molecule(VCAM)-1 (P = 0·03), with a trend for reduced intercellular cell adhesion molecule(ICAM)-1 (P = 0·09) (i.e. atherogenic markers). Modest changes in diet and physical activity result in limb-specific improvements in vascular shear profiles and reduced systemic markers of atherosclerotic risk in MetSyn patients. These data provide novel physiologic insight into adaptations that may limit the progression of atherosclerosis in patients with MetSyn.

Genomic, Transcriptomic, and Lipidomic Profiling Highlights the Role of Inflammation in Individuals With Low High-density Lipoprotein Cholesterol

Low high-density lipoprotein cholesterol (HDL-C) is associated with cardiometabolic pathologies. In this study, we investigate the biological pathways and individual genes behind low HDL-C by integrating results from 3 high-throughput data sources: adipose tissue transcriptomics, HDL lipidomics, and dense marker genotypes from Finnish individuals with low or high HDL-C (n=450). In the pathway analysis of genetic data, we demonstrate that genetic variants within inflammatory pathways were enriched among low HDL-C associated single-nucleotide polymorphisms, and the expression of these pathways upregulated in the adipose tissue of low HDL-C subjects. The lipidomic analysis highlighted the change in HDL particle quality toward putatively more inflammatory and less vasoprotective state in subjects with low HDL-C, as evidenced by their decreased antioxidative plasmalogen contents. We show that the focal point of these inflammatory pathways seems to be the HLA region with its low HDL-associated alleles also associating with more abundant local transcript levels in adipose tissue, increased plasma vascular cell adhesion molecule 1 (VCAM1) levels, and decreased HDL particle plasmalogen contents, markers of adipose tissue inflammation, vascular inflammation, and HDL antioxidative potential, respectively. In a population-based look-up of the inflammatory pathway single-nucleotide polymorphisms in a large Finnish cohorts (n=11 211), no association of the HLA region was detected for HDL-C as quantitative trait, but with extreme HDL-C phenotypes, implying the presence of low or high HDL genes in addition to the population-genomewide association studies-identified HDL genes. Our study highlights the role of inflammation with a genetic component in subjects with low HDL-C and identifies novel cis-expression quantitative trait loci (cis-eQTL) variants in HLA region to be associated with low HDL-C.

PO-33 Plasma vascular cell adhesion molecule 1, intercellular adhesion molecule 1 and osteoprotegerin levels in rectal cancer patients exposed to preoperative radiotherapy: a clinical prospective cohort study

PO-33 Plasma vascular cell adhesion molecule 1, intercellular adhesion molecule 1 and osteoprotegerin levels in rectal cancer patients exposed to preoperative radiotherapy: a clinical prospective cohort study

The relationship between plasma asymmetrical dimethyl- l-arginine and inflammation and adhesion molecule levels in subjects with normal, impaired, and diabetic glucose tolerance

Increasing evidence suggests that the postprandial state is a contributing factor to the development of atherosclerosis. To evaluate the effects of acute hyperglycemia on endothelial dysfunction and inflammation, plasma asymmetrical dimethyl- l-arginine (ADMA), intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1, and C-reactive protein (CRP) levels and secretory phospholipase A 2 (sPLA 2) activities were measured in subjects with normal (n = 35), impaired (IGT) (n = 25), and diabetic (DGT) (n = 20) glucose tolerance. At baseline, plasma ADMA, sICAM-1, and CRP concentrations and plasma sPLA 2 activities were higher in both the IGT and DGT groups than in the normal glucose tolerance group (for each comparison, each P < .001). Patients with DGT have higher plasma ADMA and sICAM-1 concentrations than patients with IGT (for each, P < .001).Two hours after glucose loading, plasma ADMA and CRP concentrations and sPLA 2 activities were significantly elevated in the 3 groups when compared with baseline levels (for each comparison, P < .001). Plasma vascular cell adhesion molecule 1 and sICAM-1 concentrations were found to be elevated from baseline levels after glucose loading in the IGT and DGT groups (for each comparison, P < .001). Correlation analysis at baseline suggested that there was a significant relationship between ADMA and inflammation and soluble adhesion markers in the studied groups. In conclusion, plasma concentrations of ADMA and of inflammation and adhesion molecules were elevated in the prediabetic state. A complex interrelation could exist between ADMA and inflammation, and mechanisms involved in endothelial dysfunction are multifactorial at the prediabetic and diabetic state.

Effect of adjuvant chemotherapy on circulating levels of ICAM, VCAM, VEGF and VEGFD in women with lymph node positive breast cancer.(NOGGO trial)

9602 Background: Intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) play a role in cell adhesion to the vascular endothelium, and may have a role in tumour cell dissemination. Expression of Vascular Endothelial Growth Factor (VEGF) has been proposed as a prognostic indicator in breast cancer, because as one of the important factors involved in angiogenesis. Our aim of the present study was to investigate the effect of chemotherapy on plasma levels of ICAM, VCAM, VEGF und VEGFD in patients with breast cancer and to compare their levels among patients with different pathological features. Methods: Patients with resected breast cancer involving 1–3 axillary lymph nodes were treated in conventional 21d intervalls with ECT (Arm A): 4x epirubicin (90mg/m2, d1) /cyclophosphamide (600 mg/m2, d1) followed by 4x paclitaxel (175 mg/m2, d1). Arm B was treated with dose-dense ET in 14 days intervalls: 4x of epirubicin (120mg/m2, d1) followed by 4x paclitaxel (175 mg/m2, 3h, d1) with obligatory G-CSF support (5 mg/kg G-CSF d5–10). Blood samples of 83 patients (45 pat. Arm A, 38 pat. Arm B) were collected before chemotherapy (group BEFORE) and after administration of 8 cycle of adjuvant chemotherapy (group AFTER). Plasma levels of ICAM, VCAM, VEGF and VEGFD were measured with commercially available ELISA assays. Results: The plasma ICAM level before chemotherapy was significantly higher (p<0,017) in postmenopausal patients. The plasma VCAM level showed significant cross-correlation with VEGF (p<0,025) and VEGF-D levels (p<0,039) before chemotherapy. In addition, ICAM und VCAM levels after chemotherapy were significantly higher than ICAM (p<0,0001) and VCAM levels (p<0,001) before chemotherapy. Measured levels of VCAM after chemotherapy were significantly higher in ARM B with dose-intensification of ET. Conclusions: We conclude there are higher levels of adhesion molecules after chemotherapy and a cross-correlation to VEGF and VEGF-D. No significant financial relationships to disclose.