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Simvastatin reduces the expression of adhesion molecules in circulating monocytes from hypercholesterolemic patients
Abdolreza Rezaie-Majd1, Gerald W Prager, Robert A Bucek
1Clinic of Internal Medicine II, Department of Angiology, University of Vienna, Vienna, Austria.
Insights
Statins, including simvastatin, reduce leukocyte adhesion molecules like ICAM-1 (CD54) and CD11a/CD18. This inhibition in patients and cell cultures may explain statins' anti-inflammatory effects and clinical benefits.
Area of Science:
- Immunology
- Pharmacology
- Cardiovascular Medicine
Background:
- Intercellular Adhesion Molecule-1 (ICAM-1/CD54) and its ligand CD11a/CD18 are key in leukocyte adhesion and transmigration.
- Statins are known to possess anti-inflammatory properties, potentially through modulating leukocyte-endothelial interactions.
Purpose of the Study:
- To investigate the in vivo effects of simvastatin on cellular adhesion molecules in hypercholesterolemic patients.
- To examine the in vitro influence of various statins on the expression of adhesion molecules and leukocyte-endothelial cell binding.
Main Methods:
- Hypercholesterolemic patients received simvastatin (20mg or 40mg daily) for 6 weeks.
- Peripheral blood mononuclear cells (PBMCs) and human umbilical vein endothelial cells (HUVECs) were analyzed for adhesion molecule expression (mRNA and surface) and binding assays.
- In vitro studies involved treating PBMCs and HUVECs with simvastatin, atorvastatin, and cerivastatin, followed by TNF-alpha stimulation.
Main Results:
- Simvastatin treatment significantly decreased CD54, CD18, and CD11a mRNA and surface expression on monocytes in hypercholesterolemic patients.
- In vitro, simvastatin, atorvastatin, and cerivastatin downregulated TNF-alpha-induced expression of CD54 and CD18/CD11a in PBMCs and HUVECs.
- All tested statins reduced the binding of PBMCs to TNF-alpha-stimulated HUVECs.
Conclusions:
- Statin-induced downregulation of CD54 and CD18/CD11a in PBMCs and HUVECs contributes to reduced adhesive function.
- This inhibition of leukocyte adhesion and transmigration likely underlies the anti-inflammatory effects and clinical benefits of statins.
Objective:
The intercellular adhesion molecule-1 (ICAM-1/CD54) and its ligand, CD11a/CD18, mediate endothelial adhesion of leukocytes and their consecutive transmigration. Anti-inflammatory effects of statins are considered to be exerted in part through inhibition of leukocyte-endothelial interactions. We investigated the in vivo effects of simvastatin treatment in hypercholesterolemic patients and the influence of various statins on expression of cellular adhesion molecules in vitro.
Methods And Results:
A total number of 107 hypercholesterolemic patients were treated with 20 mg (n=52) or 40 mg (n=55) of simvastatin daily. After 6 weeks of treatment, peripheral blood mononuclear cells (PBMCs) expressed lower amounts of CD54-, CD18-, and CD11a-mRNA compared with pretreatment values. Surface expression of CD54 and CD18/CD11a on CD14+-monocytes also decreased significantly in both groups of patients. Moreover, simvastatin, atorvastatin, and cerivastatin were found to downregulate tumor necrosis factor (TNF)-alpha-induced expression of CD54 and CD18/CD11a in isolated PBMCs obtained from normal donors as well as TNF-alpha-dependent expression of these CAMs in cultured human umbilical vein endothelial cells (HUVECs). Furthermore, all three statins were found to reduce the binding of PBMCs to TNF-alpha-stimulated HUVECs in vitro.
Conclusions:
Statin-induced inhibition of expression of CD54 and CD18/CD11a in PBMCs and HUVECs with consecutive loss of adhesive function may contribute to the anti-inflammatory effects of these drugs and some of their beneficial clinical activities.