Novel Function of Cysteine‐rich Secretory Protein from
            Naja Atra
            Venom:CRISP‐a induces pro‐inflammatory responses of vascular endothelial cells

Objective TGR5, a membrane-bound, G-protein-coupled receptor for bile acids, is known to be involved in regulation of energy homeostasis and inflammation. However, little is known about the function of TGR5 in vascular endothelial cells. In the present study, we examined whether TGR5 agonism represents anti-inflammatory effects in vascular endothelial cells focusing on nitric oxide (NO) production. Methods and Results In human umbilical vein endothelial cells (HUVECs), treatment with taurolithocholic acid (TLCA), which has the highest affinity to TGR5 among various bile acids, significantly reduced tumor necrosis factor (TNF)-α-induced vascular cell adhesion molecule (VCAM)-1 protein expression and adhesion of human monocytes, U937. These effects were abrogated by a NO synthase (NOS) inhibitor, N G -Monomethyl-L-arginine (L-NMMA). In bovine aortic endothelial cells (BAECs), treatment with TLCA as well as lithocholic acid, which also has high affinity to TGR5, significantly increased the NO production. In contrast, deoxycholic acid and chenodeoxycholic acid, which possess low affinity to TGR5, did not affect the NO production. Gene depletion of TGR5 by siRNA transfection abolished TLCA-induced NO production in BAECs. TLCA-induced NO production was also observed in HUVECs measured as intracellular cGMP accumulation. We next investigated the signal pathways responsible for the TLCA-induced NO production in endothelial cells. Treatment with TLCA increased endothelial NOS (eNOS) ser1177 phosphorylation in HUVECs. This response was accompanied by increased Akt ser473 phosphorylation and intracellular Ca 2+ ([Ca 2+ ] i ). Treatment with phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, or blockade of calcium channel with La 3+ , significantly decreased TLCA-induced eNOS ser1177 phosphorylation and subsequent NO production. Conclusion These results indicate that TGR5 agonism can mediate anti-inflammatory responses by suppressing VCAM-1 expression and monocytes adhesion to endothelial cells. This function is dependent on NO production via Akt activation and [Ca 2+ ] i increase.

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Novel control of cAMP-regulated transcription in vascular endothelial cells

Biochemical Society Transactions ◽

10.1042/bst20110606 ◽

2012 ◽

Vol 40 (1) ◽

pp. 1-5 ◽

Cited By ~ 9

Author(s):

Gillian R. Milne ◽

Timothy M. Palmer ◽

Stephen J. Yarwood

Keyword(s):

Endothelial Cells ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Vascular Endothelial Cells ◽

Inflammatory Diseases ◽

Circulatory System ◽

Vascular Endothelial ◽

Protective Mechanisms ◽

Enhancer Binding Protein ◽

Developed World

Chronic inflammatory diseases, such as atherosclerosis, are a major cause of death and disability in the developed world. In this respect, although cholesterol obviously plays a predominant role in atherosclerosis, targeting inflammation at lesion sites may be just as important. Indeed, elevated IL-6 (interleukin 6) levels are as strongly associated with coronary heart disease as increased cholesterol. We have been investigating novel cAMP-regulated pathways that combat the action of pro-inflammatory cytokines, such as IL-6 and leptin, in the VECs (vascular endothelial cells) of the circulatory system. In this respect, we have begun to unravel new molecular mechanisms by which the cAMP/Epac1 (exchange protein directly activated by cAMP 1)/Rap1 pathway can initiate a rigorous programme of protective anti-inflammatory responses in VECs. Central to this is the coupling of cAMP elevation to the mobilization of two C/EBP (CCAAT/enhancer-binding protein) family transcription factors, resulting in the induction of the SOCS3 (suppressor of cytokine signalling 3) gene, which attenuates pro-inflammatory cytokine signalling in VECs. These novel ‘protective’ mechanisms of cAMP action will inform the development of the next generation of pharmaceuticals specifically designed to combat endothelial inflammation associated with cardiovascular disease.

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Inorganic polyphosphate elicits pro-inflammatory responses through activation of the mammalian target of rapamycin complexes 1 and 2 in vascular endothelial cells

Journal of Thrombosis and Haemostasis ◽

10.1111/jth.12899 ◽

2015 ◽

Vol 13 (5) ◽

pp. 860-871 ◽

Cited By ~ 35

Author(s):

S. M. Hassanian ◽

P. Dinarvand ◽

S. A. Smith ◽

A. R. Rezaie

Keyword(s):

Endothelial Cells ◽

Inflammatory Responses ◽

Vascular Endothelial Cells ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Vascular Endothelial ◽

Inorganic Polyphosphate

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Mediators released from LPS-challenged lungs induce inflammatory responses in liver vascular endothelial cells and neutrophilic leukocytes

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00278.2009 ◽

2009 ◽

Vol 297 (6) ◽

pp. G1066-G1076 ◽

Cited By ~ 20

Author(s):

N. Markovic ◽

L. A. McCaig ◽

J. Stephen ◽

S. Mizuguchi ◽

R. A. W. Veldhuizen ◽

...

Keyword(s):

Endothelial Cells ◽

Inflammatory Response ◽

Inflammatory Responses ◽

Vascular Endothelial Cells ◽

Vascular Endothelial ◽

Ros Production ◽

Proinflammatory Mediators ◽

Primary Mouse ◽

Mouse Lungs

The systemic inflammatory response plays an important role in the progression of acute lung injury (ALI) to multiple organ dysfunction syndrome (MODS). However, the role of lung-derived inflammatory mediators in induction of the inflammatory response in remote organs is poorly understood. To address the above, we investigated the effects of lung inflammation on induction of inflammatory response(s) in the liver in vitro. Inflammation in mouse lungs was induced by intranasal administration of lipopolysaccharide (LPS; 1 mg/ml) followed by mechanical ventilation using the isolated perfused mouse lung method to obtain and characterize lung perfusate from the pulmonary circulation. LPS administration to mouse lungs resulted in an increased release of inflammation-relevant cytokines and chemokines into the perfusate (Luminex assay) compared with the saline-controls. Subsequently, primary mouse liver vascular endothelial cells (LVEC) or mouse polymorphonuclear leukocytes (PMN) in vitro were stimulated with the perfusate obtained from saline- or LPS-challenged lungs and assessed for various inflammation-relevant end points. The obtained results indicate that stimulation of LVEC with perfusate obtained from LPS-challenged lungs results in 1) reactive oxygen species (ROS) production; 2) activation of NF-κB; and 3) expression of E-selectin, ICAM-1, and VCAM-1 and a subsequent increase in PMN rolling and adhesion to LVEC. In addition, perfusate from LPS-challenged lung induced activation of PMN with respect to increased ROS production and upregulation of cell surface levels of adhesion molecules MAC-1 and VLA-4. Heat-inactivation of the perfusate obtained from LPS-challenged lungs was very effective in suppressing increased proadhesive phenotype (i.e., E-selectin and ICAM-1 expression) in LVEC, whereas targeted inhibition (immunoneutralization) of TNF-α and/or IL-6 in LPS-lung perfusate had no effect. Taken together, these findings indicate that multiple proinflammatory mediators (proteinaceous in nature) released from inflamed lungs act synergistically to induce systemic activation of circulating PMN and promote inflammatory responses in liver vascular endothelial cells.

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Peroxisome Proliferator‐Activated Receptor gamma (PPARgamma) ligand, 15d‐PGJ2, represses pro‐inflammatory responses in vascular endothelial cells: The role of nitric oxide

The FASEB Journal ◽

10.1096/fasebj.20.5.a1165 ◽

2006 ◽

Vol 20 (5) ◽

Author(s):

John A Polikandriotis ◽

Jinah Hwang ◽

Mauricio Rojas ◽

C Michael Hart

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Inflammatory Responses ◽

Vascular Endothelial Cells ◽

Peroxisome Proliferator ◽

Vascular Endothelial ◽

Peroxisome Proliferator Activated Receptor

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Cordycepin Attenuates Palmitic Acid-Induced Inflammation and Apoptosis of Vascular Endothelial Cells through Mediating PI3K/Akt/eNOS Signaling Pathway

The American Journal of Chinese Medicine ◽

10.1142/s0192415x21500804 ◽

2021 ◽

pp. 1-20

Author(s):

Chang-Wen Ku ◽

Tsung-Jung Ho ◽

Chih-Yang Huang ◽

Pei-Ming Chu ◽

Hsiu-Chung Ou ◽

...

Keyword(s):

Endothelial Cells ◽

Palmitic Acid ◽

Signaling Pathway ◽

Inflammatory Responses ◽

Vascular Endothelial Cells ◽

Cordyceps Sinensis ◽

Ros Generation ◽

Vascular Endothelial ◽

Protective Effects ◽

Anti Inflammatory

A well-known medicinal mushroom in the field of traditional Chinese medicine, Cordyceps sinensis, is a rare natural-occurring entomopathogenic fungus, and it typically grows at high altitudes on the plateau of the Himalayan. Previous studies indicated that cordycepin, the main bioactive chemical of Cordyceps sinensis, has very potent anticancer, anti-oxidant and anti-inflammatory activities. However, its protective effects against atherosclerotic changes in vascular endothelial cells have not been fully elucidated. In this study, we showed that pretreatment with cordycepin significantly attenuated palmitic acid (PA)-induced cytotoxicity, reactive oxygen species (ROS) generation, and inflammatory responses. We found that PA decreased phosphorylation of Akt, eNOS, and bioavailability of nitric oxide (NO), which in turn activated NF-[Formula: see text]B and the downstream inflammatory responses. All these detrimental events were markedly blocked by pretreatment with cordycepin. Moreover, cordycepin ameliorated destabilization of mitochondrial permeability, cytosolic calcium rises, and apoptotic features caused by PA. In addition, all these anti-inflammatory and anti-apoptosis effects of cordycepin were found to be inhibited by the PI3K and eNOS inhibitor, suggesting that its anti-atherosclerotic effects may partially be mediated by the PI3K/Akt/eNOS signaling pathway.

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Expression of functional CD40 by vascular endothelial cells.

Journal of Experimental Medicine ◽

10.1084/jem.182.1.33 ◽

1995 ◽

Vol 182 (1) ◽

pp. 33-40 ◽

Cited By ~ 286

Author(s):

D Hollenbaugh ◽

N Mischel-Petty ◽

C P Edwards ◽

J C Simon ◽

R W Denfeld ◽

...

Keyword(s):

T Cells ◽

Endothelial Cells ◽

Adhesion Molecule ◽

Inflammatory Disease ◽

Vascular Endothelium ◽

Cell Activation ◽

Inflammatory Responses ◽

Vascular Endothelial Cells ◽

Intercellular Adhesion Molecule ◽

Vascular Endothelial

The interaction between activated vascular endothelium and T cells has been shown to play an important role in the recruitment and activation of T cells at sites of inflammation. Here we report the expression of CD40 by vascular endothelial cells and its regulation by inflammatory agents. Using the soluble recombinant CD40 ligand, sgp39, we show that the interaction of CD40 with its ligand can lead to endothelial cell activation, which in turn leads to leukocyte adhesion. This adhesion is partly mediated by the expression of E-selectin. In addition to E-selectin expression, sgp39 induces the expression of intercellular adhesion molecule 1 and augments the tumor necrosis factor alpha-induced expression of vascular cell adhesion molecule 1. The effects of sgp39 on endothelial cells can be blocked with anti-gp39 monoclonal antibody (mAb), anti-CD40 mAb, or soluble CD40. Staining of tissues from healthy human skin using anti-CD40 mAb showed very weak expression of CD40 by the endothelium, while skin involved in inflammatory disease showed marked upregulation of CD40 expression. These studies suggest that interactions between cell surface proteins expressed by activated T cells with their receptors on vascular endothelium can stimulate the vasculature at sites of inflammation and may be involved in normal inflammatory responses and in inflammatory disease.

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