scholarly journals Atherogenic Lipoprotein(a) Increases Vascular Glycolysis, Thereby Facilitating Inflammation and Leukocyte Extravasation

2020 ◽  
Vol 126 (10) ◽  
pp. 1346-1359 ◽  
Author(s):  
Johan G. Schnitzler ◽  
Renate M. Hoogeveen ◽  
Lubna Ali ◽  
Koen H.M. Prange ◽  
Farahnaz Waissi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transendothelial Migration ◽  
Intercellular Adhesion Molecule ◽  
Phospholipid Content ◽  
Intercellular Adhesion Molecule 1 ◽  
Lipoprotein A ◽  
Positron Emission ◽  
And Migration ◽  
The Impact ◽  
Arterial Endothelial Cells

Rationale: Patients with elevated levels of lipoprotein(a) [Lp(a)] are hallmarked by increased metabolic activity in the arterial wall on positron emission tomography/computed tomography, indicative of a proinflammatory state. Objective: We hypothesized that Lp(a) induces endothelial cell inflammation by rewiring endothelial metabolism. Methods and Results: We evaluated the impact of Lp(a) on the endothelium and describe that Lp(a), through its oxidized phospholipid content, activates arterial endothelial cells, facilitating increased transendothelial migration of monocytes. Transcriptome analysis of Lp(a)-stimulated human arterial endothelial cells revealed upregulation of inflammatory pathways comprising monocyte adhesion and migration, coinciding with increased 6-phophofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)-3–mediated glycolysis. ICAM (intercellular adhesion molecule)-1 and PFKFB3 were also found to be upregulated in carotid plaques of patients with elevated levels of Lp(a). Inhibition of PFKFB3 abolished the inflammatory signature with concomitant attenuation of transendothelial migration. Conclusions: Collectively, our findings show that Lp(a) activates the endothelium by enhancing PFKFB3-mediated glycolysis, leading to a proadhesive state, which can be reversed by inhibition of glycolysis. These findings pave the way for therapeutic agents targeting metabolism aimed at reducing inflammation in patients with cardiovascular disease.

Cardiac myocytes exposed to anoxia-reoxygenation promote neutrophil transendothelial migration

2001 ◽  
Vol 281 (1) ◽  
pp. H440-H447 ◽  
Author(s):  
Tao Rui ◽  
Gediminas Cepinskas ◽  
Qingping Feng ◽  
Ye-Shih Ho ◽  
Peter R. Kvietys
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cardiac Myocytes ◽  
Manganese Superoxide Dismutase ◽  
Oxidant Stress ◽  
Transendothelial Migration ◽  
Polymorphonuclear Neutrophil ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Chemotactic Gradient

The goal of the present study was to assess whether cardiac myocytes exposed to anoxia-reoxygenation (A/R) could generate a chemotactic gradient for polymorphonuclear neutrophil (PMN) transendothelial migration. Exposure of neonatal mouse cardiac myocytes to A/R induced an oxidant stress in the myocytes. Supernatants obtained from A/R-conditioned myocytes promoted mouse PMN migration across mouse myocardial endothelial cell monolayers. This increase in PMN transendothelial migration could be prevented if catalase or a platelet-activating factor (PAF) antagonist was added to the supernatants before assay. Supernatants from A/R-conditioned myocytes activated endothelial cells by inducing an intracellular oxidant stress. The oxidant stress and PMN transendothelial migration induced by supernatants from A/R-conditioned myocytes were substantially reduced when endothelial cells derived from manganese superoxide dismutase overexpressing mice were used in the assays. Supernatants from A/R-conditioned myocytes also increased endothelial cell surface levels of E-selectin and intercellular adhesion molecule-1. Our results indicate that cardiac myocytes exposed to A/R can generate a chemotactic gradient, presumably due to production and release of stable oxidants and PAF. The ability of supernatants from A/R-conditioned myocytes to promote PMN transendothelial migration was largely dependent on induction of an oxidant stress in endothelial cells. In addition, these supernatants also induced a proadhesive phenotype in the endothelial cells.

Endothelial tetraspanin microdomains regulate leukocyte firm adhesion during extravasation

Blood ◽  
2005 ◽  
Vol 105 (7) ◽  
pp. 2852-2861 ◽  
Author(s):  
Olga Barreiro ◽  
María Yáñez-Mó ◽  
Mónica Sala-Valdés ◽  
María Dolores Gutiérrez-López ◽  
Susana Ovalle ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Leukocyte Adhesion ◽  
Transendothelial Migration ◽  
Intercellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Glutathione S Transferase ◽  
Large Extracellular Loop ◽  
And Migration ◽  
Cell Adhesion Molecule 1

AbstractTetraspanins associate with several transmembrane proteins forming microdomains involved in intercellular adhesion and migration. Here, we show that endothelial tetraspanins relocalize to the contact site with transmigrating leukocytes and associate laterally with both intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Alteration of endothelial tetraspanin microdomains by CD9–large extracellular loop (LEL)–glutathione S–transferase (GST) peptides or CD9/CD151 siRNA oligonucleotides interfered with ICAM-1 and VCAM-1 function, preventing lymphocyte transendothelial migration and increasing lymphocyte detachment under shear flow. Heterotypic intercellular adhesion mediated by VCAM-1 or ICAM-1 was augmented when expressed exogenously in the appropriate tetraspanin environment. Therefore, tetraspanin microdomains have a crucial role in the proper adhesive function of ICAM-1 and VCAM-1 during leukocyte adhesion and transendothelial migration.

scholarly journals A Role for the αvβ3 Integrin in the Transmigration of Monocytes

1998 ◽  
Vol 142 (2) ◽  
pp. 595-607 ◽  
Author(s):  
Dheepika Weerasinghe ◽  
Kevin P. McHugh ◽  
Frederick P. Ross ◽  
Eric J. Brown ◽  
Roland H. Gisler ◽  
...  
Keyword(s):  
Integrin Αvβ3 ◽  
Transendothelial Migration ◽  
Intercellular Adhesion Molecule ◽  
Αvβ3 Integrin ◽  
Intercellular Adhesion Molecule 1 ◽  
Migration Assay ◽  
Monocyte Migration ◽  
Dependent Cell ◽  
And Migration

The β2 integrins and intercellular adhesion molecule-1 (ICAM-1) are important for monocyte migration through inflammatory endothelium. Here we demonstrate that the integrin αvβ3 is also a key player in this process. In an in vitro transendothelial migration assay, monocytes lacking β3 integrins revealed weak migratory ability, whereas monocytes expressing β3 integrins engaged in stronger migration. This migration could be partially blocked by antibodies against the integrin chains αL, β2, αv, or IAP, a protein functionally associated with αvβ3 integrin. Transfection of β3 integrin chain cDNA into monocytes lacking β3 integrins resulted in expression of the αvβ3 integrin and conferred on these cells an enhanced ability to transmigrate through cell monolayers expressing ICAM-1. These monocytes also engaged in αLβ2-dependent locomotion on recombinant ICAM-1 which was enhanced by αvβ3 integrin occupancy. Antibodies against IAP were able to revert this αvβ3 integrin-dependent cell locomotion to control levels. Finally, adhesion assays revealed that occupancy of αvβ3 integrin could decrease monocyte binding to ICAM-1. In conclusion, we show that αvβ3 integrin modulates αLβ2 integrin-dependent monocyte adhesion to and migration on ICAM-1. This could represent a novel mechanism to promote monocyte motility on vascular ICAM-1 and initiate subsequent transendothelial migration.

scholarly journals PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

2017 ◽  
Vol 114 (10) ◽  
pp. 2693-2698 ◽  
Author(s):  
Marianne Strazza ◽  
Inbar Azoulay-Alfaguter ◽  
Michael Peled ◽  
Alan V. Smrcka ◽  
Edward Y. Skolnik ◽  
...  
Keyword(s):  
T Cell ◽  
Small Gtpase ◽  
The Body ◽  
Delayed Type Hypersensitivity ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Regional Lymph Nodes ◽  
Lymphocyte Adhesion ◽  
Enzymatic Function ◽  
And Migration

Regulation of integrins is critical for lymphocyte adhesion to endothelium and migration throughout the body. Inside-out signaling to integrins is mediated by the small GTPase Ras-proximate-1 (Rap1). Using an RNA-mediated interference screen, we identified phospholipase Cε 1 (PLCε1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1α)-induced Rap1 activation. We have shown that SDF-1α-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor. We identified that PLCε1 was necessary for SDF-1α-induced adhesion using shear stress, cell morphology alterations, and crawling on intercellular adhesion molecule 1 (ICAM-1)–expressing cells. Structure–function experiments to separate the dual-enzymatic function of PLCε1 uncover necessary contributions of the CDC25, Pleckstrin homology, and Ras-associating domains, but not phospholipase activity, to this pathway. In the mouse model of delayed type hypersensitivity, we have shown an essential role for PLCε1 in T-cell migration to inflamed skin, but not for cytokine secretion and proliferation in regional lymph nodes. Our results reveal a signaling pathway where SDF-1α induces T-cell adhesion through activation of PLCε1, suggesting that PLCε1 is a specific potential target in treating conditions involving migration of T cells to inflamed organs.

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