scholarly journals Residues within a conserved amino acid motif of domains 1 and 4 of VCAM-1 are required for binding to VLA-4.

1994 ◽  
Vol 125 (1) ◽  
pp. 215-222 ◽  
Author(s):  
R H Vonderheide ◽  
T F Tedder ◽  
T A Springer ◽  
D E Staunton
Keyword(s):  
Amino Acids ◽  
Cell Adhesion ◽  
Amino Acid ◽  
Adhesion Molecule ◽  
Binding Sites ◽  
Tumor Cell Line ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Conserved Motif ◽  
Late Antigen

Vascular cell adhesion molecule 1 (VCAM-1), a member of the Ig superfamily originally identified on activated endothelium, binds to the integrin very late antigen-4 (VLA-4), also known as alpha 4 beta 1 or CD49d/CD29, to support cell-cell adhesion. Studies based on cell adhesion to two alternatively spliced forms of VCAM-1 or to chimeric molecules generated from them and intercellular adhesion molecule-1 (ICAM-1) have demonstrated two VLA-4 binding sites on the predominate form of VCAM-1. Here, we studied VLA-4-dependent adhesion of the lymphoid tumor cell line Ramos to cells expressing wild type and mutant forms of VCAM-1. Results based on domain deletion mutants demonstrated the existence and independence of two VLA-4-binding sites located in the first and fourth domains of VCAM-1. Results based on amino acid substitution mutants demonstrated that residues within a linear sequence of six amino acids found in both domain 1 and 4 were required for VLA-4 binding to either domain. Five of these amino acids represent a conserved motif also found in ICAM domains. We propose that integrin binding to these Ig-like domains depends on residues within this conserved motif. Specificity of integrin binding to Ig-like domains may be regulated by a set of nonconserved residues distinct from the conserved motif.

Local Delivery of Ibuprofen via Controlled-release Polymers Prevents Angiographic Vasospasm in a Monkey Model of Subarachnoid Hemorrhage

2005 ◽  
Vol 57 (suppl_1) ◽  
pp. 184-190 ◽  
Author(s):  
Gustavo Pradilla ◽  
Quoc-Anh Thai ◽  
Federico G. Legnani ◽  
Richard E. Clatterbuck ◽  
Philippe Gailloud ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Subarachnoid Hemorrhage ◽  
Controlled Release ◽  
Adhesion Molecule ◽  
Subarachnoid Space ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Cynomolgus Monkeys ◽  
Monkey Model ◽  
Angiographic Vasospasm

Abstract OBJECTIVE: Adhesion and migration of leukocytes into the periadventitial space play a role in the pathophysiology of vasospasm after subarachnoid hemorrhage (SAH). Intercellular adhesion molecule-1 is a determinant cell adhesion molecule involved in this process. Ibuprofen has been shown to inhibit intercellular adhesion molecule-1 upregulation and prevent vasospasm in animal models of SAH. In this study, we report the toxicity and efficacy of locally delivered ibuprofen incorporated into controlled-release polymers to prevent vasospasm in a monkey model of SAH. METHODS: Ibuprofen was incorporated into ethylene-vinyl acetate (EVAc) polymers at 45% loading (wt:wt). For the toxicity study, cynomolgus monkeys (n = 5) underwent surgical implantation of either blank/EVAc polymers (n = 3) or 45% ibuprofen/EVAc polymers (n = 2) in the subarachnoid space, were followed up for 13 weeks, and were killed for histopathological analysis. For the efficacy study, cynomolgus monkeys (n = 14) underwent cerebral angiography 7 days before and 7 days after surgery and SAH and were randomized to receive either a 45% ibuprofen/EVAc polymer (n = 7; mean dose of ibuprofen, 6 mg/kg) or blank EVAc polymers (n = 7) in the subarachnoid space. Angiographic vasospasm was determined by digital image analysis. Student's t test was used for analysis. RESULTS: Animals implanted with ibuprofen polymers showed no signs of local or systemic toxicity. Animals treated with ibuprofen polymers had 91 ± 9% lumen patency of the middle cerebral artery, compared with 53 ± 11% of animals treated with blank/EVAc polymers (P < 0.001). CONCLUSION: Ibuprofen polymers are safe and prevent angiographic vasospasm after SAH in the monkey model. These findings support the role of cell adhesion molecules and inflammation in the pathophysiology of vasospasm.

scholarly journals Distinct Roles For ROCK1 and ROCK2 in the Regulation of Oxldl-Mediated Endothelial Dysfunction

2018 ◽  
Vol 49 (2) ◽  
pp. 565-577 ◽  
Author(s):  
Lei Huang ◽  
Fan Dai ◽  
Lian Tang ◽  
Xiaofeng Bao ◽  
Zhaoguo Liu ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Endothelial Dysfunction ◽  
Adhesion Molecules ◽  
Adhesion Molecule ◽  
Cell Apoptosis ◽  
Umbilical Vein ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Rock Inhibitor ◽  
Vimentin Expression

Background/Aims: This study used Rho-associated protein kinase (ROCK) isoform-selective suppression or a ROCK inhibitor to analyze the roles of ROCK1 and ROCK2 in regulating endothelial dysfunction triggered by oxidized low-density lipoprotein (oxLDL). Methods: ROCK1 or ROCK2 expression in human umbilical vein endothelial cells (HUVECs) was suppressed by small interfering RNA (siRNA). HUVECs were pretreated with 30 μM Y27632 (pan ROCK inhibitor) for 30 min before exposure to 200 μg/mL oxLDL for an additional 24 h. Cell viability was determined by the MTT assay, and cell apoptosis was evaluated by the TUNEL assay. Protein expression and phosphorylation were assessed by Western blot analysis. The morphology of total and phosphorylated vimentin (p-vimentin) and the co-localization of vimentin with vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) were detected by the immunofluorescence assay. The adhesion of promonocytic U937 cells to HUVECs was observed by light microscopy. Results: ROCK2 suppression or Y27632 treatment, rather than ROCK1 deletion, effectively reduced endothelial cell apoptosis and preserved cell survival. ROCK2 suppression exhibited improved vimentin and p-vimentin cytoskeleton stability and decreased vimentin cleavage by attenuating caspase-3 activity. In addition, increased p-vimentin expression induced by oxLDL was significantly inhibited by ROCK2 deletion or Y27632 treatment. In contrast, ROCK1 suppression showed no obvious effects on the vimentin cytoskeleton, but significantly regulated the expression of adhesion molecules. Endothelial ICAM-1 or VCAM-1 expression induced by oxLDL was obviously inhibited by ROCK1 suppression or Y27632 treatment. Moreover, the expression of ICAM-1 induced by oxLDL could also be reduced by ROCK2 suppression. Furthermore, ROCK2 deficiency or Y27632 treatment inhibited the redistribution of adhesion molecules and their co-localization with vimentin caused by oxLDL. These effects resulted in the significant inhibition of monocyte-endothelial adhesion induced by oxLDL. Conclusion: The results of this study support the novel concept that ROCK1 is involved in oxLDL-induced cell adhesion by regulating adhesion molecule expression, whereas ROCK2 is required for both endothelial apoptosis and adhesion by regulating both the vimentin cytoskeleton and adhesion molecules. Consequently, ROCK1 and ROCK2 have distinct roles in the regulation of oxLDL-mediated endothelial dysfunction.

Abstract 13301: Methylome-wide Association With Soluble Cell Adhesion Molecules Among Monozygotic Twins

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Yan Sun ◽  
Jack Goldberg ◽  
Dean P Jones ◽  
Viola Vaccarino
Keyword(s):  
Cell Adhesion ◽  
Endothelial Function ◽  
Adhesion Molecules ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecules ◽  
Critical Role ◽  
Epigenetic Mechanism ◽  
Intercellular Adhesion Molecule ◽  
Soluble Form ◽  
Intercellular Adhesion Molecule 1

Introduction: Inflammation plays a critical role in the pathogenesis of cardiovascular disease. Epigenetic mechanisms, including DNA methylation (DNAm), is critical in the regulation of inflammatory genes, and can be influenced by inflammation. The soluble form of cell adhesion molecules, including vascular adhesion molecule 1 (sVCAM1), intercellular adhesion molecule 1 (sICAM1), and P-selectin (sP-selectin), are established biomarkers for inflammation and endothelial function, and are linked to cardiovascular events. Methods: To identify epigenetic markers associated with inflammation and endothelial function, we conducted a methylome-wide association study and investigated over 480,000 DNAm sites of peripheral blood cells from 140 monozygotic (MZ) middle-aged male twins from the Emory Twin Study. Results: Using two randomly selected subsets consisting of unrelated subjects, we identified and replicated 69 and 23 DNAm sites significantly associated with sVCAM1, and sICAM1 respectively, adjusted for multiple testing, but none for sP-selectin. All 23 sICAM1-associated DNAm sites were also associated with sVCAM1, including sites on gene ANKRD11 (P=1.51х10-21, 2.62х10-20), KDM2B (P=1.52х10-21, 9.13х10-17), CAPS (P=2.81х10-20, 3.17х10-18), and CUX1 (P=7.63х10-20, 2.84х10-19). They jointly explained 54% and 40% of variance in sVCAM1 and sICAM1 respectively. Two DNAm sites, located on UNC5D and TMEM125, were also significant comparing MZ twins who were phenotypically discordant for both sICAM1 (P=1.79х10-7, 2.78х10-6) and sVCAM1 (P=1.70х10-9, 1.71х10-7). Conclusions: These results suggest that sVCAM1 and sICAM1, but not sP-selectin, may share common pathophysiology in inflammation and endothelial function via an epigenetic mechanism in leukocytes. In addition, the epigenetic association with inflammation may be driven by unshared environmental exposures.

scholarly journals Osteopontin Predicts Three-Month Outcome in Stroke Patients Treated by Reperfusion Therapies

2020 ◽  
Vol 9 (12) ◽  
pp. 4028
Author(s):  
Elena Meseguer ◽  
Devy Diallo ◽  
Julien Labreuche ◽  
Hugo Charles ◽  
Sandrine Delbosc ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Tissue Remodeling ◽  
Intercellular Adhesion Molecule ◽  
Cathepsin S ◽  
Intercellular Adhesion Molecule 1 ◽  
Stroke Patients ◽  
Monocyte Chemoattractant Protein 1 ◽  
Significance Level ◽  
Matrix Metallopeptidase

Establishing a prognosis at hospital admission after stroke is a major challenge. Inflammatory processes, hemostasis, vascular injury, and tissue remodeling are all involved in the early response to stroke. This study analyzes whether 22 selected biomarkers, sampled at admission, predict clinical outcomes in 153 stroke patients treated by thrombolysis and mechanical endovascular treatment (MET). Biomarkers were related to hemostasis (u-plasminogen activator/urokinase (uPA/urokinase), serpin E1/PAI-1, serpin C1/antithrombin-III, kallikrein 6/neurosin, alpha 2-macroglobulin), inflammation[myloperoxidase (MPO), chemokine ligand 2/monocyte chemoattractant protein-1 chemokine (CCL2/MCP-1), adiponectin, resistin, cell-free DNA (cDNA), CD40 Ligand (CD40L)], endothelium activation (Vascular cell adhesion protein 1 (VCAM-1) intercellular adhesion molecule 1 (ICAM-1), platelet endothelial cell adhesion molecule 1 (CD31/PECAM-1)], and tissue remodeling (total cathepsin S, osteopontin, cystatin C, neuropilin-1, matrix metallopeptidase 2 (MMP-2), matrix metallopeptidase 3 (MMP-3), matrix metallopeptidase 9 (MMP-9), matrix metallopeptidase 13 (MMP-13)]. Correlations between their levels and excellent neurological improvement (ENI) at 24 h and good outcomes (mRS 0–2) at three months were tested. Osteopontin and favorable outcomes reached the significance level (p = 0.008); the adjusted OR per SD increase in log-transformed osteopontin was 0.34 (95%CI, 0.18–0.62). The relationship between total cathepsin S and MPO with ENI, was borderline of significance (p = 0.064); the adjusted OR per SD increase in log-transformed of total cathepsin S and MPO was 0.54 (95%CI, 0.35–0.81) and 0.51 (95%CI, 0.32–0.80), respectively. In conclusion, osteopontin levels predicted three-month favorable outcomes, supporting the use of this biomarker as a complement of clinical and radiological parameters for predicting stroke prognosis.

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