Modulation of Adhesion Molecule Expression on Endothelial Cells by Verapamil and Other Ca++ Channel Blockers

doi:10.1016/S0171-2985(11)80266-4

Immunobiology

Volume 191, Issue 1, August 1994, Pages 38-51

https://doi.org/10.1016/S0171-2985(11)80266-4 Get rights and content

Abstract

Cytokine-induced expression of adhesion molecules on leukocytes and endothelial cells (EC) is a crucial point in the process of organ transplant rejection. It has been shown that protein kinase C (PKC) is involved in this activation process. Verapamil and other calcium channel blockers seem to possess immunosuppressive qualities in vivo and in vitro; some authors suggested that this is due to PKC- or calmodulin-antagonism. Thus our objectives were to further investigate the second-messenger systems involved in the stimulation of EC and to analyze whether the beneficial influence of calcium channel blockers on the outcome of transplantation is due to impaired expression of adhesion molecules on EC..

Our results, obtained in an in vitro model using human umbilical vein EC, show that IL-1-induced expression of intercellular adhesion molecule-1 (ICAM-1) is in part mediated by PKC and that parallel activation of calmodulin is required. Expression of ICAM-1 was reduced to 38.5% by PKC-inhibitor H7 and to 77.2% by calmodulininhibitor W7. In addition, data on the intracellular events in TNF-α-induced expression of vascular cell adhesion molecule-1 (VCAM-1) is presented, showing that both PKC and, to a higher extent, calmodulin, are involved in this process. Expression of VCAM-1 was reduced to 63.7% by H7 and to 27.7% by W7. IL-1-induced expression of endothelial leukocyte adhesion molecule-1 (ELAM-1) is PKC-dependent but insensitive to blocking of calmodulin.

Though activation of adhesion molecule expression utilizes PKC and/or calmodulin as second-messenger pathways the investigated calcium channel blockers verapamil (R- and S-enantiomers), diltiazem and Ro 40-5967 failed to inhibit adhesion molecule expression.Surprisingly, higher concentrations of verapamil (> 12.5 μ/ml) or Ro 40-5967 (5 μg/ml) significantly enhanced IL-1-induced expression of ELAM-1. ICAM-1-expression was also enhanced by verapamil, but not by Ro 40-5967 or diltiazem. This enhancement was only seen if verapamil was added maximally one hour after the cytokine stimulus indicating that transcriptional modulation is responsible for the observed effects. Our findings indicate that calcium channel blockers have an immunomodulating effect independent of adhesion molecule expression.

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Background. Heparin-coated circuits reduce the inflammatory response to cardiopulmonary bypass in adult patients; however, little is known about its effects in the pediatric population. Two studies were performed to assess this technology’s impact on inflammation and clinical outcomes.
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Conclusions. Heparin-bonded circuits significantly reduce cytokines and complement during cardiopulmonary bypass and lower interleukin levels postbypass; they were also associated with improved pulmonary and coagulation function. Heparin-bonded circuits ameliorate the systemic inflammatory response in pediatric patients from cardiopulmonary bypass.
Effects of exercise on circulating vascular adhesion molecules in healthy men
1997, Immunobiology
Based on previous studies showing an increase in circulating soluble intercellular adhesion molecule-1 (siCAM-1) after exercise, we hypothesized that exercise may also increase serum levels of the vascular cell adhesion molecule-1 (sVCAM-1) and sE-selectin. In a prospective controlled clinical trial, serum levels of sE-selectin, siCAM-1 and sVAM-1 were measured before and after two different exercise protocols in healthy untrained men.
Lactate levels increased up to 12.7 mmol/L (95% confidence interval: 10.1–15.9) and 3.6 mmol/L (CI: 2.4–4.7) after ergometry and after an one hour endurance exercise at 60% of the maximal work intensity, respectively (p = 0.028 vs baseline and controls). The maximal increase in lymphocyte counts of 106% (CI: 63–146), which was only of short duration, was higher immediately after ergometry as compared to that observed after endurance exercise (p = 0.028). However, the maximal increase in neutrophil counts of 178% (CI: 120–298) which was seen at 2 hours after endurance exercise was higher than that seen after ergometry (p = 0.028).
In contrast, only small changes of circulating adhesion molecules were seen immediately after ergometry: siCAM-1 increased by 11% (CI: 4–25; p = 0.028), and similar tendencies were also observed for sVCAM-1 and sE-selectin. No other consistent and time-dependent changes of circulating adhesion molecules were observed and all differences and changes were ≤11%.
In sum our study provides evidence that recreational sporting activities in untrained healthy subjects at normal altitude have little influence on serum levels of the circulating vascular adhesion molecules sE-selectin, sVCAM-1 or siCAM-1.
Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VCAM-1, and ICAM-1 expression in human endothelial cells
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Most studies on the antipsoriatic mode of action of dimethylfumarate focused on its antiproliferative effects in keratinocytes. Because inflammatory skin diseases are associated with an upregulation of endothelial cell adhesion molecules and because the presence of inflammatory cells in dermis and epidermis is considered an important feature in psoriasis, we tested the effect of DMF on cytokine-induced adhesion molecule expression in HUVEC, usingin situELISA and Northern blotting. Dimethylfumarate inhibited ICAM-1, VCAM-1, and E-selectin expression and reduced adhesion of U937 cells to stimulated HUVEC. Monoethylfumarate and fumaric acid had no effect. Similar inhibitory effects for DMF on VCAM-1 expression were observed after stimulation of HUVEC with LPS, PMA, IL-4, and IL-1α or in combinations with TNFα. These data are in agreement with previously reported effects of DMF on intracellular thiol levels and inhibition of NF-κB activation. The inhibitory effect on cytokine-induced endothelial adhesion molecule expression may represent another target of dimethylfumarate in psoriasis.
Intracellular signaling of tumor necrosis factor-α in brain microvascular endothelial cells is mediated by a protein tyrosine kinase and protein kinase C-dependent pathway
1996, Journal of Neuroimmunology
The intracellular signaling pathways responsible for tumor necrosis factor (TNF)-α stimulation of lymphocyte adhesion to brain microvascular endothelial cells (BMEC) were studied using inhibitors of protein kinase C (bisindolylmaleimide HCl, H-7, or staurosporine), or protein tyrosine kinase (genistein). Each of these blocked the ability of BMEC to respond to TNF-α. In contrast, BMEC treated with H-89, an inhibitor of protein kinase A, or the adenylate cyclase inhibitor, dideoxyadenosine, responded normally to TNF-α. Forskolin, an adenylate cyclase agonist, significantly increased lymphocyte adhesion to BMEC. These data indicate that intracellular signaling by TNF-α in BMEC is mediated through a protein kinase C and tyrosine kinase dependent pathway.
Disseminated intravascular coagulation phenotype is regulated by the TRPM7 channel during sepsis
2023, Biological Research
Inhibitory effects of verapamil isomers on the proliferation of choroidal endothelial cells
2006, Graefe's Archive for Clinical and Experimental Ophthalmology

View all citing articles on Scopus

^a: Dr. Nils P.Hailer, Klinik für Allgemein- and Abdominalchirurgie, Transplantationsimmunologisches Labor, Eg7, Haus 23A, Klinikum der Johann-Wolfgang-GoetheUniversität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany

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Modulation of Adhesion Molecule Expression on Endothelial Cells by Verapamil and Other Ca++ Channel Blockers

Abstract

Adhesion receptors of the immune system

Nature

The role of endothelial cells in inflammation

Transplantation

Lymphocyte interactions with endothelial cells

Immunol. Today

Cyclosporine in cadaveric renal transplantation: three-year follow-up of a European multicenter trial

Transplant. Proc.

Liver transplantation 1980 with particular reference to cyclosporine-A

Transplant. Proc.

Cardiac transplantation 1980. Transplant

Proc.

Molecular mechanisms of immunosuppressive agents

Transplant. Proc. 24, No 4, Suppl

Cyclosporine nephrotoxicity: pathogenesis, prophylaxis, therapy, and prognosis

Am. J. Kid. Dis.

Prevention of acute cyclosporine-induced renal blood flow inhibition and improved immunosuppression with verapamil

Transplantation

Improved outcome of cadaveric renal transplantation due to calcium channel blockers

Transplantation

Excellent outcome with a calcium channel blocker-supplemented immunosuppressive regimen in cadaveric renal transplantation

Transplantation

The effect of verapamil on cellular uptake, organ distribution, and pharmacology of cyclosporine

Transplantation

Effect of the Calcium Channel Blockers S-, R-Verapamil and Ro 40-5967 on Adhesion and Migration Properties of Lymphocytes Acting on Human Vascular Endothelium. Endothelium

Additive effects of calcium antagonists on cyclosporin A-induced inhibition of T-cell proliferation

Nephrol. Dial. Transplant.

Modulation of Adhesion Molecule Expression on Endothelial Cells by Verapamil and Other Ca⁺⁺ Channel Blockers