Transient Receptor Potential Melastatin 4 (TRPM4) Contributes to High Salt Diet-Mediated Early-Stage Endothelial Injury
Xiaoqing DingTao BanZengyan LiuJie LouLiang‐Liang TangJiaxin WangWenfeng ChuDan ZhaoBin‐Lin SongZhi‐Ren Zhang
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Background/Aims: The present study investigated whether the transient receptor potential melastatin 4 (TRPM4) channel plays a role in high salt diet (HSD)-induced endothelial injuries. Methods: Western blotting and immunofluorescence were used to examine TRPM4 expression in the mesenteric endothelium of Dahl salt-sensitive (SS) rats fed a HSD. The MTT, TUNEL, and transwell assays were used to evaluate the cell viability, cell apoptosis, and cell migration, respectively, of human umbilical vein endothelial cells (HUVECs). Enzyme-linked immunosorbent assays were used to determine the concentrations of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion protein 1 (VCAM-1), and E-selectin. Carboxy-H2DCFDA, a membrane-permeable reactive oxygen species (ROS)-sensitive fluorescent probe, was used to detect intracellular ROS levels. Results: TRPM4 was mainly expressed near the plasma membrane of mesenteric artery endothelial cells, and its expression level increased in SS hypertensive rats fed a HSD. Its protein expression was significantly upregulated upon treatment with exogenous hydrogen peroxide (H2O2) and aldosterone in cultured HUVECs. Cell viability decreased upon treatment with both agents in a concentration-dependent manner, which could be partially reversed by 9-phenanthrol, a specific TRPM4 inhibitor. Exogenous H2O2 induced apoptosis, enhanced cell migration, and increased the release of adhesion molecules, including ICAM-1, VCAM-1, and E-selectin, all of which were significantly attenuated upon treatment with 9-phenanthrol. Aldosterone and H2O2 induced the accumulation of intracellular ROS, which was significantly inhibited by 9-phenanthrol, suggesting that oxidative stress is one of the mechanisms underlying aldosterone-induced endothelial injury. Conclusions: Given the fact that oxidative stress and high levels of circulating aldosterone are present in hypertensive patients, we suggest that the upregulation of TRPM4 in the vascular endothelium may be involved in endothelial injuries caused by these stimuli.Keywords:
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Objective:To examine the effects of endothelial microparticles(EMPs)on the expressions of vascular cell adhesion molecule 1(VCAM-1) and intercellular adhesion molecule(ICAM-1) in human umbilical vein endothelial cells(HUVECs).Methods:HUVECs at passage 4 to 5 were incubated for 24 h with EMPs(0,1×102,1×103,1×104,1×105/ml).Quantitative real-time polymerase chain reaction and Western blotting were used to detect expressions of mRNA and protein of ICAM-1 and VCAM-1 respectively.Results:Both two detection methods showed that EMPs stimulation significantly induced the mRNA and protein expressions of VCAM-1 and ICAM-1 in HUVECs in a dose-dependent manner.Conclusion:EMPs can induce the expressions of VCAM-1 and ICAM-1 in a dose-dependent manner.These findings suggest that EMPs may have adverse effects in modulating inflammatory response in atherosclerosis.
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The dual radiolabeled mAb technique was used to quantify the constitutive and induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the microvasculature of different organs of the mouse. The constitutive expression of both adhesion molecules varied significantly between tissues, with ICAM-1 levels consistently higher than VCAM-1 in all tissues studied. Following systemic administration of endotoxin (LPS), an increased surface expression of both adhesion molecules occurred in most organs, with the largest increases for ICAM-1 (2 to 3x increase) noted in the heart, small intestine, and brain, while heart and small intestine exhibited the largest increases in LPS-induced VCAM-1 expression (2 to 5x increase). These responses occurred in the face of an unaltered expression of platelet endothelial cell adhesion molecule-1 (PECAM-1) in all tissues. TNF-alpha also elicited an increased expression of both adhesion molecules, with initial increases noted at 2 to 5 h, peak levels at 5 to 9 h, and a sustained elevation above baseline at 24 h. The TNF-alpha-induced increases in both ICAM-1 and VCAM-1 were dose dependent, with significant up-regulation noted at 5 microg/kg and maximal increases occurring at 10 to 25 microg/kg. These studies indicate that while there are significant quantitative differences in constitutive and induced expression of murine ICAM-1 and VCAM-1, the kinetics and dose-response characteristics of the two adhesion molecules to TNF-alpha are qualitatively similar.
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Intercellular adhesion molecules 1(ICAM-1) and vascular cell adhesion molecule 1(VCAM-1) play important roles in the inflammatory process of cerebral ischemic injury.The expression of ICAM-1 and VCAM-1 increases following cerebral ischemia;ICAM-1 and VCAM-1 promote ischemic inflammation through mediating leukocytes adhesion to the endothelial cells and eventually migration into brain tissue;the inhibition of the overexpression and effect of ICAM-1 and VCAM-1 can reduce cerebral ischemic injury.
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Intercellular adhesion molecules 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCM-l) play important roles in the inflammatory process of cerebral ischemic injury. The expression of ICAM-l and VCAM-1 increases following cerebral ischemia; ICAM1 and VCAM-l promote ischemic inflammation through mediating leukocytes adhesion to the endothelial cells and eventually migration into brain tissue; the inhibition of the overexpression and effect of ICAM-l and VCAM-l can reduce cerebral ischemic injury.
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Objective:To explore the effects of ICAM 1 and VCAM 1 on the adherence of rIL 2 activated umbilical lymphocytes to human umbilical vein endothelial cells(HUVEC). Methods:① Activated umbilical lymphocytes were put on the surface of the cultured HUVEC sheet.After a certain period of time, the adherence rate was calculated. ② The phenotypes of adherent lymphocytes were studied with APAAP method. Results:①ICAM 1 and VCAM 1 McAb obviously lower the adherent activity of activated lymphocytes.The former decreased the adherent rate from 56.54% to 41.6%(P0.05),and the latter to 30.3%(P0.05). ② ICAM 1 McAb lowered the adherence of CD8 +,raised the adherence of CD4 +,and have no significant effect on CD56 +,while VCAM 1 McAb increased the adherence of CD8 +,lowered the adherence of CD56 + and have no significant effect on CD4 +. Conclusion:The adherent activity of activated lymphocytes is stronger obviously than that of unactivated ones.ICAM 1 and VCAM 1 may participate in the regulation of the adherence of activated lymphocytes to HUVEC.
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