scholarly journals GPR55 Antagonist CID16020046 Protects against Atherosclerosis Development in Mice by Inhibiting Monocyte Adhesion and Mac-1 Expression

2021 ◽  
Vol 22 (23) ◽  
pp. 13084
Author(s):  
Seung-Jin Lee ◽  
Dong-Soon Im
Keyword(s):  
Endothelial Cells ◽  
High Fat Diet ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Vascular Endothelial ◽  
Monocyte Adhesion ◽  
High Fat ◽  
Potent Agonist ◽  
Atherosclerosis Development ◽  
Umbilical Vein Endothelial Cells

GPR55 recognizes several lipid molecules such as lysophosphatidylinositol. GPR55 expression was reported in human monocytes. However, its role in monocyte adhesion and atherosclerosis development has not been studied. The role of GPR55 in monocyte adhesion and atherosclerosis development was investigated in human THP-1 monocytes and ApoE−/− mice using O-1602 (a potent agonist of GPR55) and CID16020046 (a specific GPR55 antagonist). O-1602 treatment significantly increased monocyte adhesion to human umbilical vein endothelial cells, and the O-1602-induced adhesion was inhibited by treatment with CID16020046. O-1602 induced the expression of Mac-1 adhesion molecules, whereas CID16020046 inhibited this induction. Analysis of the promoter region of Mac-1 elucidated the binding sites of AP-1 and NF-κB between nucleotides −750 and −503 as GPR55 responsive elements. O-1602 induction of Mac-1 was found to be dependent on the signaling components of GPR55, that is, Gq protein, Ca2+, CaMKK, and PI3K. In Apo−/− mice, administration of CID16020046 ameliorated high-fat diet-induced atherosclerosis development. These results suggest that high-fat diet-induced GPR55 activation leads to the adhesion of monocytes to endothelial cells via induction of Mac-1, and CID16020046 blockage of GPR55 could suppress monocyte adhesion to vascular endothelial cells through suppression of Mac-1 expression, leading to protection against the development of atherosclerosis.

scholarly journals GPR55 antagonist CID16020046 protects against atherosclerosis development in mice by inhibiting monocyte adhesion and Mac-1 expression

2021 ◽  
Author(s):  
Seung-Jin Lee ◽  
DONG-SOON IM
Keyword(s):  
Endothelial Cells ◽  
High Fat Diet ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Monocyte Adhesion ◽  
High Fat ◽  
Atherosclerosis Development ◽  
Proinflammatory Role ◽  
Umbilical Vein Endothelial Cells

Background and Purpose: GPR55 is a G protein-coupled receptor that recognizes several lipid molecules. GPR55 expression in human monocytes and its proinflammatory role lead us to investigate the role of GPR55 in monocyte adhesion and atherosclerosis development. Experimental Approach: We investigated monocyte adhesion in human THP-1 monocytes and atherosclerosis development in ApoE-/- mice by using O-1602 (a potent agonist of GPR55), CID16020046 (a specific GPR55 antagonist), and a high-fat diet-induced atherosclerosis model. Key Results: In human THP-1 monocytes, treatment with O-1602 significantly increased monocyte adhesion to human umbilical vein endothelial cells (HUVECs), and the O-1602-induced adhesion was inhibited by treatment with CID16020046. O-1602 induced the expression of Mac-1 adhesion molecules, whereas CID16020046 inhibited this induction. Analysis of the promoter region of Mac-1 elucidated the binding sites of AP-1 and NF-κB between nucleotides -750 and -503 as GPR55 responsive elements. Furthermore, O-1602 induction of Mac-1 through AP-1 and NF-B was found to be dependent on the signaling components of GPR55, that is, Gq protein, Ca2+, CaMKK, and PI3K. In an in vivo study of high-fat diet-induced atherosclerosis in ApoE-/- mice, administration of CID16020046 ameliorated atherosclerosis development. These results suggest that high-fat diet-induced GPR55 activation leads to adhesion of monocytes to endothelial cells via induction of Mac-1, and CID16020046 blockage of GPR55 could suppress monocyte adhesion to vascular endothelial cells through suppression of Mac-1 expression, leading to protection against the development of atherosclerosis. Conclusions: This report suggests that GPR55 may be a therapeutic target for atherosclerosis development.

scholarly journals Citrus bergamiaRisso Elevates Intracellular Ca2+in Human Vascular Endothelial Cells due to Release of Ca2+from Primary Intracellular Stores

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Purum Kang ◽  
Seung Ho Han ◽  
Hea Kyung Moon ◽  
Jeong-Min Lee ◽  
Hyo-Keun Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Channel Blocker ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Concentration Dependent Manner ◽  
Carbonyl Cyanide ◽  
Intracellular Ca ◽  
Umbilical Vein Endothelial Cells

The purpose of the present study is to examine the effects of essential oil ofCitrus bergamiaRisso (bergamot, BEO) on intracellular Ca2+in human umbilical vein endothelial cells. Fura-2 fluorescence was used to examine changes in intracellular Ca2+concentration[Ca2+]i. In the presence of extracellular Ca2+, BEO increased[Ca2+]i, which was partially inhibited by a nonselective Ca2+channel blocker La3+. In Ca2+-free extracellular solutions, BEO increased[Ca2+]iin a concentration-dependent manner, suggesting that BEO mobilizes intracellular Ca2+. BEO-induced[Ca2+]iincrease was partially inhibited by a Ca2+-induced Ca2+release inhibitor dantrolene, a phospholipase C inhibitor U73122, and an inositol 1,4,5-triphosphate (IP3)-gated Ca2+channel blocker, 2-aminoethoxydiphenyl borane (2-APB). BEO also increased[Ca2+]iin the presence of carbonyl cyanide m-chlorophenylhydrazone, an inhibitor of mitochondrial Ca2+uptake. In addition, store-operated Ca2+entry (SOC) was potentiated by BEO. These results suggest that BEO mobilizes Ca2+from primary intracellular stores via Ca2+-induced and IP3-mediated Ca2+release and affect promotion of Ca2+influx, likely via an SOC mechanism.

scholarly journals CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1645
Author(s):  
Ikjun Lee ◽  
Shuyu Piao ◽  
Seonhee Kim ◽  
Harsha Nagar ◽  
Su-Jeong Choi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Dihydrofolate Reductase ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Plasma Concentrations ◽  
Vascular Endothelial ◽  
Cell Dysfunction ◽  
Key Enzyme ◽  
Umbilical Vein Endothelial Cells ◽  
Folate Cycle

Elevated plasma homocysteine levels can induce vascular endothelial dysfunction; however, the mechanisms regulating homocysteine metabolism in impaired endothelial cells are currently unclear. In this study, we deleted the essential mitoribosomal gene CR6 interacting factor 1 (CRIF1) in human umbilical vein endothelial cells (HUVECs) and mice to induce endothelial cell dysfunction; then, we monitored homocysteine accumulation. We found that CRIF1 downregulation caused significant increases in intracellular and plasma concentrations of homocysteine, which were associated with decreased levels of folate cycle intermediates such as 5-methyltetrahydrofolate (MTHF) and tetrahydrofolate (THF). Moreover, dihydrofolate reductase (DHFR), a key enzyme in folate-mediated metabolism, exhibited impaired activity and decreased protein expression in CRIF1 knockdown endothelial cells. Supplementation with folic acid did not restore DHFR expression levels or MTHF and homocysteine concentrations in endothelial cells with a CRIF1 deletion or DHFR knockdown. However, the overexpression of DHFR in CRIF1 knockdown endothelial cells resulted in decreased accumulation of homocysteine. Taken together, our findings suggest that CRIF1-deleted endothelial cells accumulated more homocysteine, compared with control cells; this was primarily mediated by the disruption of DHFR expression.

scholarly journals TKI-Resistant Renal Cancer Secretes Low-Level Exosomal miR-549a to Induce Vascular Permeability and Angiogenesis to Promote Tumor Metastasis

2021 ◽  
Vol 9 ◽  
Author(s):  
Zuodong Xuan ◽  
Chen Chen ◽  
Wenbin Tang ◽  
Shaopei Ye ◽  
Jianzhong Zheng ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Permeability ◽  
Renal Cancer ◽  
Kinase Inhibitors ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Endothelial Permeability ◽  
Vascular Endothelial ◽  
Cell Renal Cell Carcinoma ◽  
Umbilical Vein Endothelial Cells

Tyrosine kinase inhibitors (TKI)-resistant renal cancer is highly susceptible to metastasis, and enhanced vascular permeability promotes the process of metastasis. To evaluate the effect of cancer-derived exosomes on vascular endothelial cells and clarify the mechanism of metastasis in TKI-resistant renal cancer, we studied the crosstalk between clear cell renal cell carcinoma (ccRCC) cells and human umbilical vein endothelial cells (HUVECs). Exosomes from ccRCC cells enhanced the expression of vascular permeability-related proteins. Compared with sensitive strains, exosomes from resistant strains significantly enhanced vascular endothelial permeability, induced tumor angiogenesis and enhanced tumor lung metastasis in nude mice. The expression of miR-549a is lower in TKI-resistant cells and exosomes, which enhanced the expression of HIF1α in endothelial cells. In addition, TKI-resistant RCC cells reduced nuclear output of pre-miR-549a via the VEGFR2-ERK-XPO5 pathway, and reduced enrichment of mature miR-549a in cytoplasm, which in turn promoted HIF1α expression in RCC, leading to increased VEGF secretion and further activated VEGFR2 to form a feedback effect. miR-549a played an important role in the metastasis of renal cancer and might serve as a blood biomarker for ccRCC metastasis and even had the potential of becoming a new drug to inhibit TKI-resistance.

scholarly journals Dexmedetomidine Attenuates Monocyte-Endothelial Adherence via Inhibiting Connexin43 on Vascular Endothelial Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Yunfei Chai ◽  
Runying Yu ◽  
Yong Liu ◽  
Sheng Wang ◽  
Dongdong Yuan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Vascular Endothelial ◽  
Cx43 Expression ◽  
Multiple Organs ◽  
Key Factor ◽  
Umbilical Vein Endothelial Cells

Current studies have identified the multifaceted protective functions of dexmedetomidine on multiple organs. For the first time, we clarify effects of dexmedetomidine on monocyte-endothelial adherence and whether its underlying mechanism is relative to connexin43 (Cx43), a key factor regulating monocyte-endothelial adherence. U937 monocytes and human umbilical vein endothelial cells (HUVECs) were used to explore monocyte-endothelial adherence. Two special siRNAs were designed to knock down Cx43 expression on HUVECs. U937-HUVEC adhesion, adhesion-related molecules, and the activation of the MAPK (p-ERK1/2, p-p38, and p-JNK1/2) signaling pathway were detected. Dexmedetomidine, at its clinically relevant concentrations (0.1 nM and 1 nM), was given as pretreatments to HUVECs. Its effects on Cx43 and U937-HUVEC adhesion were also investigated. The results show that inhibiting Cx43 on HUVECs could attenuate the contents of MCP-1, soluble ICAM-1 (sICAM-1), soluble VCAM-1 (sVCAM-1), and the nonprocessed variants of the adhesion molecules ICAM-1 and VCAM-1 and ultimately result in U937-HUVEC adhesion decrease. Meanwhile, the activation of MAPKs was also inhibited. U0126 (inhibiting p-ERK1/2) and SB202190 (inhibiting p38) decreased the contents of MCP-1, sICAM-1, and sVCAM-1, but SP600125 (inhibiting p-JNK1/2) had none of these effects. ICAM-1 and VCAM-1 could be regulated in a similar way. Dexmedetomidine pretreatment inhibited Cx43 on HUVECs, the activation of MAPKs, and U937-HUVEC adhesion. Therefore, we conclude that dexmedetomidine attenuates U937-HUVEC adhesion via inhibiting Cx43 on HUVECs modulating the activation of MAPK signaling pathways.

scholarly journals miR-101-3p induces vascular endothelial cell dysfunction by targeting tet methylcytosine dioxygenase 2

2020 ◽  
Vol 52 (2) ◽  
pp. 180-191 ◽  
Author(s):  
Qiaoli Chen ◽  
Xiaoye Li ◽  
Lingjun Kong ◽  
Qing Xu ◽  
Zi Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Vascular Endothelial Cell ◽  
Nuclear Factor Κb ◽  
Vascular Endothelial ◽  
Ros Production ◽  
Cell Dysfunction ◽  
Umbilical Vein Endothelial Cells

Abstract Endothelial cell (EC) dysfunction represents an early key event in atherosclerosis. Recently, MicroRNAs have been demonstrated to regulate EC function. miR-101-3p has been discovered to regulate cell apoptosis and proliferation in cardiovascular diseases. Therefore, the aim of the current study was to clarify whether miR-101-3p regulates the dysfunction of vascular endothelial cells. In this study, the transfection of human umbilical vein endothelial cells (HUVECs) with miR-101-3p mimic induced reactive oxygen species (ROS) production, EC dysfunction, and activated nuclear factor-κB (NF-κB), whereas transfection with miR-101-3p inhibitor alleviated these events. The antioxidant N-acetylcysteine alleviated miR-101-3p-induced EC dysfunction. Moreover, we observed that miR-101-3p inhibited the expression of tet methylcytosine dioxygenase 2 (TET2) at the posttranscriptional level, resulting in increased ROS production and activated NF-κB. TET2 overexpression inhibited ROS production, EC dysfunction, and NF-κB activation in miR-101-3p-transfected HUVECs. These results indicate that miR-101-3p induces EC dysfunction by targeting TET2, which regulates ROS production, EC dysfunction, and NF-κB activation. Taken together, our current study reveals a novel pathway associated with EC dysfunction. The modulation of miR-101-3p and TET2 expression levels may serve as a potential target for therapeutic strategies for atherosclerosis.

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