scholarly journals Insulin Sensitivity Is Retained in Mice with Endothelial Loss of Carcinoembryonic Antigen Cell Adhesion Molecule 1

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2093
Author(s):  
Harrison T. Muturi ◽  
Saja S. Khuder ◽  
Hilda E. Ghadieh ◽  
Emily L. Esakov ◽  
Hyelim Noh ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Insulin Sensitivity ◽  
Visceral Obesity ◽  
Matrix Metalloproteases ◽  
Endothelial Barrier ◽  
Barrier Dysfunction ◽  
Insulin Transport ◽  
Metabolic Role ◽  
Normal Glucose ◽  
Cell Adhesion Molecule 1

CEACAM1 regulates endothelial barrier integrity. Because insulin signaling in extrahepatic target tissues is regulated by insulin transport through the endothelium, we aimed at investigating the metabolic role of endothelial CEACAM1. To this end, we generated endothelial cell-specific Ceacam1 null mice (VECadCre+Cc1fl/fl) and carried out their metabolic phenotyping and mechanistic analysis by comparison to littermate controls. Hyperinsulinemic-euglycemic clamp analysis showed intact insulin sensitivity in VECadCre+Cc1fl/fl mice. This was associated with the absence of visceral obesity and lipolysis and normal levels of circulating non-esterified fatty acids, leptin, and adiponectin. Whereas the loss of endothelial Ceacam1 did not affect insulin-stimulated receptor phosphorylation, it reduced IRS-1/Akt/eNOS activation to lower nitric oxide production resulting from limited SHP2 sequestration. It also reduced Shc sequestration to activate NF-κB and increase the transcription of matrix metalloproteases, ultimately inducing plasma IL-6 and TNFα levels. Loss of endothelial Ceacam1 also induced the expression of the anti-inflammatory CEACAM1-4L variant in M2 macrophages in white adipose tissue. Together, this could cause endothelial barrier dysfunction and facilitate insulin transport, sustaining normal glucose homeostasis and retaining fat accumulation in adipocytes. The data assign a significant role for endothelial cell CEACAM1 in maintaining insulin sensitivity in peripheral extrahepatic target tissues.

TNF-alpha induces endothelial cell F-actin depolymerization, new actin synthesis, and barrier dysfunction

1993 ◽  
Vol 264 (4) ◽  
pp. C894-C905 ◽  
Author(s):  
S. E. Goldblum ◽  
X. Ding ◽  
J. Campbell-Washington
Keyword(s):  
Endothelial Cell ◽  
Barrier Function ◽  
Endothelial Barrier ◽  
Tnf Alpha ◽  
Vascular Endothelial ◽  
Gap Formation ◽  
Endothelial Barrier Function ◽  
Barrier Dysfunction ◽  
Necrosis Factor Alpha ◽  
Actin Depolymerization

Tumor necrosis factor-alpha (TNF-alpha) influences pulmonary vascular endothelial barrier function in vitro. We studied whether recombinant TNF-alpha (rTNF-alpha) regulates endothelial barrier function through actin reorganization. Postconfluent bovine pulmonary artery endothelial cell monolayers were exposed to human rTNF-alpha (1,000 U/ml) and evaluated for 1) transendothelial [14C]albumin flux, 2) F-actin organization with fluorescence microscopy, 3) F-actin quantitation by spectrofluorometry, and 4) monomeric G-actin levels by the deoxyribonuclease I inhibition assay. rTNF-alpha induced increments in [14C]albumin flux (P < 0.04) and intercellular gap formation at > or = 2-6 h. During this same time, the endothelial F-actin pool decreased (P = 0.0064), with reciprocal increases in the G-actin pool (P < 0.0001). Prior F-actin stabilization with phallicidin protected against the rTNF-alpha-induced increments in G-actin (P < 0.002) as well as changes in barrier function (P < 0.01). Prior protein synthesis inhibition enhanced the rTNF-alpha-induced decrement in F-actin (P < 0.0001), blunted the G-actin increment (P < 0.002), and increased rTNF-alpha-induced changes in endothelial barrier function (P < 0.003). Therefore, rTNF-alpha induces pulmonary vascular endothelial F-actin depolymerization, intercellular gap formation, and barrier dysfunction. rTNF-alpha also increased total actin (P < 0.02) and new actin synthesis (P < 0.002), which may be a compensatory endothelial cell response to rTNF-alpha-induced F-actin depolymerization.

scholarly journals Linagliptin improves high glucose-induced glomerular endothelial hyper- permeability through AMPK activation and RhoA/ROCK suppression

2021 ◽  
Author(s):  
Jianhui Chen ◽  
Xianfan Li ◽  
Zengpu Yu ◽  
Xiaolin Chen
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
High Glucose ◽  
Fluorescence Probe ◽  
Endothelial Barrier ◽  
Protective Effects ◽  
Ampk Activation ◽  
Barrier Dysfunction ◽  
Rock Inhibitor

Abstract OBJECTIVEHyperglycemia is a major cause of albuminuria relevant to glomerular endothelial dysfunction of the kidney in diabetes mellitus. Linagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to have pleiotropic protective effects to improve albuminuria and endothelial dysfunction in diabetic conditions. The purpose of this research was to investigate the molecular mechanism by which linagliptin improves human renal glomerular endothelial cells (HRGECs) barrier dysfunction caused by hyperglycemia.MATERIALS AND METHODSWe examined the DPP-4 activity, the transendothelial electrical resistance of the monolayer in HRGECs, and the horseradish peroxidase–albumin leakage after the treatment with high glucose (HG) in the presence or absence of linagliptin preincubation. The distribution of F-actin remodeling was detected by a fluorescence probe. The phosphorylation of myosin light chain (MLC), AMPK, and RhoA activity were evaluated in the endothelial cells by Western blotting. The effects of inhibition AMPK or RhoA/ROCK pathway on linagliptin-mediated protective effect on the endothelial barrier in HG status were observed.RESULTSHG caused MLC-dependent reorganization of F-actin, leading to endothelial barrier disruption. However, these changes in HRGECs were attenuated by the Rho-dependent kinase (ROCK) inhibitor Y-27632 or linagliptin. The phospho-MLC (pMLC) activated in HRGECs was regulated by RhoA/ROCK signaling. AMPK activation participated in the repair process of HG-induced RhoA-dependent endothelial cell hyperpermeability by linagliptin . Similarly , AMPK activation by linagliptin attenuated HG-induced RhoA dependent F-actin rearrangement and endothelial cell barrier dysfunction, whereas compoud C diminished the effect of linagliptin. CONCLUSIONSOur data showed that HG led to increases in the activity of RhoA and DPP-4. These changes resulted in the rearrangement of endothelial cell cytoskeleton and the dysfunction of the glomerular endothelial barrier, which were mediated by MLC. The present study revealed a novel mechanism of linagliptin-mediated AMPK activation in preventing RhoA-dependent F-actin cytoskeleton rearrangement and reduced glomerular endothelial barrier permeability in diabetic conditions.

scholarly journals Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema

2016 ◽  
Vol 311 (1) ◽  
pp. L39-L47 ◽  
Author(s):  
Jinyan Yu ◽  
Zhongsen Ma ◽  
Sreerama Shetty ◽  
Mengshi Ma ◽  
Jian Fu
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Pulmonary Edema ◽  
Fiber Formation ◽  
Cell Junctions ◽  
Endothelial Barrier ◽  
Barrier Dysfunction ◽  
Barrier Disruption ◽  
Endothelial Barrier Dysfunction ◽  
Tnf Α

Lung endothelial damage contributes to the pathogenesis of acute lung injury. New strategies against lung endothelial barrier dysfunction may provide therapeutic benefits against lung vascular injury. Cell-cell junctions and microtubule cytoskeleton are basic components in maintaining endothelial barrier integrity. HDAC6, a deacetylase primarily localized in the cytoplasm, has been reported to modulate nonnuclear protein function through deacetylation. Both α-tubulin and β-catenin are substrates for HDAC6. Here, we examined the effects of tubastatin A, a highly selective HDAC6 inhibitor, on TNF-α induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema. Selective HDAC6 inhibition by tubastatin A blocked TNF-α-induced lung endothelial cell hyperpermeability, which was associated with increased α-tubulin acetylation and microtubule stability. Tubastatin A pretreatment inhibited TNF-α-induced endothelial cell contraction and actin stress fiber formation with reduced myosin light chain phosphorylation. Selective HDAC6 inhibition by tubastatin A also induced β-catenin acetylation in human lung endothelial cells, which was associated with increased membrane localization of β-catenin and stabilization of adherens junctions. HDAC6 knockdown by small interfering RNA also prevented TNF-α-induced barrier dysfunction and increased α-tubulin and β-catenin acetylation in endothelial cells. Furthermore, in a mouse model of endotoxemia, tubastatin A was able to prevent endotoxin-induced deacetylation of α-tubulin and β-catenin in lung tissues, which was associated with reduced pulmonary edema. Collectively, our data indicate that selective HDAC6 inhibition by tubastatin A is a potent approach against lung endothelial barrier dysfunction.

scholarly journals Endotoxin-Neutralizing Protein Protects against Endotoxin-Induced Endothelial Barrier Dysfunction

1998 ◽  
Vol 66 (4) ◽  
pp. 1400-1407 ◽  
Author(s):  
Douglas D. Bannerman ◽  
Michael J. Fitzpatrick ◽  
Dell Y. Anderson ◽  
Apurba K. Bhattacharjee ◽  
Thomas J. Novitsky ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Tyrosine Phosphorylation ◽  
Lipid A ◽  
Protein A ◽  
Endothelial Barrier ◽  
Barrier Dysfunction ◽  
Recombinant Peptide ◽  
Gram Negative ◽  
Actin Organization ◽  
Cell Monolayers

ABSTRACT Bacterial lipopolysaccharide induces tyrosine phosphorylation of paxillin, actin reorganization, and opening of the transendothelial paracellular pathway through which macromoles flux. In this study, lipid A was shown to be the bioactive portion of the lipopolysaccharide molecule responsible for changes in endothelial barrier function. We then studied whether endotoxin-neutralizing protein, a recombinant peptide that is derived from Limulus antilipopolysaccharide factor and targets lipid A, could block the effects of lipopolysaccharide on protein tyrosine phosphorylation, actin organization, and movement of 14C-bovine serum albumin across bovine pulmonary artery endothelial cell monolayers. In the presence of serum, a 6-h exposure to lipopolysaccharide (10 ng/ml) increased transendothelial 14C-albumin flux compared to the simultaneous media control. Coadministration of endotoxin-neutralizing protein (≥10 ng/ml) with lipopolysaccharide (10 ng/ml) protected against lipopolysaccharide-induced barrier dysfunction. This protection was dose dependent, conferring total protection at endotoxin-neutralizing protein/lipopolysaccharide ratios of ≥10:1. Similarly, endotoxin-neutralizing protein was capable of blocking the lipopolysaccharide-induced endothelial cell responses that are prerequisite to barrier dysfunction, including tyrosine phosphorylation of paxillin and actin depolymerization. Finally, endotoxin-neutralizing protein cross-protected against lipopolysaccharide derived from diverse gram-negative bacteria. Thus, endotoxin-neutralizing protein offers a novel therapeutic intervention for the vascular endothelial dysfunction of gram-negative sepsis and its attendant endotoxemia.

Differential Expression of Platelet-Endothelial Cell Adhesion Molecule-1 (PECAM-1) in Murine Tissues

1998 ◽  
Vol 5 (2-3) ◽  
pp. 179-188 ◽  
Author(s):  
MICHAEL J EPPIHIMER ◽  
J A N I C E RUSELL ◽  
R O B E R T LANGLEY ◽  
G I N A VALLIEN ◽  
DONALD C ANDERSON ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Endothelial Cell ◽  
Differential Expression ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Endothelial Cell Adhesion Molecule ◽  
Platelet Endothelial Cell Adhesion ◽  
Cell Adhesion Molecule 1 ◽  
Endothelial Cell Adhesion
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