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Simvastatin inhibits leukocyte-endothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 1999 Dec; Vol. 19 (12), pp. 2894-900. - Publication Year :
- 1999
-
Abstract
- Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to lower serum cholesterol levels and normalize endothelial cell function. Moreover, HMG-CoA reductase inhibitors exert beneficial effects in coronary artery and cerebrovascular diseases. We examined the effects of simvastatin on leukocyte-endothelial cell interaction in vivo by intravital microscopy. Simvastatin (12.5 or 25 microg per rat) was given 18 hours before study. Superfusion with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 50 micromol/L) significantly increased leukocyte rolling from 12+/-2 to 60+/-8 leukocytes per minute, increased adherence to the mesenteric endothelium from 1.8+/-0.5 to 17+/-1.2 leukocytes per 100 microm of venular length, and raised leukocyte transmigration from 2.5+/-1.0 to 10+/-2 leukocytes per perivessel area (P<0.01). Similar results were obtained with thrombin (0.5 U/mL) superfusion of the mesentery. In contrast, pretreatment with simvastatin (25 microg per rat IP) significantly attenuated L-NAME-stimulated leukocyte rolling, to 12+/-2 (P<0.01); adherence, to 5+/-0.5 leukocytes per 100 microm (P<0.01); and leukocyte transmigration, to 3.5+/-1.5 leukocytes per perivessel area (P<0.01). Similar results were obtained in thrombin-superfused mesenteries. Moreover, immunohistochemical analysis demonstrated significantly increased P-selectin expression on the mesenteric venular endothelium after superfusion with either L-NAME (P<0.01) or thrombin (P<0.01), which was significantly attenuated by simvastatin. These results clearly demonstrate that simvastatin is a potent and effective endothelium-protective agent that reduces leukocyte-endothelial cell interactions independently of its well-known lipid-lowering effects. This effect was found to be at least partially mediated via downregulation of P-selectin expression on the microvascular endothelium. Thus, HMG-CoA reductase inhibitors like simvastatin have important anti-inflammatory effects besides their well-known lipid-lowering action.
- Subjects :
- Animals
Blood Pressure
Cell Communication drug effects
Cell Movement immunology
Cholesterol blood
Endothelium, Vascular immunology
Endothelium, Vascular metabolism
Enzyme Inhibitors pharmacology
Glucose pharmacology
Hemostatics pharmacology
Leukocytes immunology
Male
Mesenteric Veins cytology
Mesenteric Veins immunology
Microscopy methods
NG-Nitroarginine Methyl Ester pharmacology
Nitric Oxide metabolism
P-Selectin analysis
P-Selectin metabolism
Rats
Rats, Sprague-Dawley
Thrombin pharmacology
Tromethamine pharmacology
Vasculitis immunology
Vasculitis metabolism
Venules chemistry
Venules cytology
Venules metabolism
Anticholesteremic Agents pharmacology
Endothelium, Vascular cytology
Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology
Leukocytes cytology
Simvastatin pharmacology
Vasculitis drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1079-5642
- Volume :
- 19
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 10591666
- Full Text :
- https://doi.org/10.1161/01.atv.19.12.2894