Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2894-2900
© 1999 American Heart Association, Inc.
Vascular Biology |
Simvastatin Inhibits Leukocyte–Endothelial Cell Interactions and Protects Against Inflammatory Processes in Normocholesterolemic Rats
From the Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa.
Correspondence to Dr Allan M. Lefer, Department of Physiology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107-6799. E-mail Allan.M.Lefer{at}mail.tju.edu
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 µg per rat) was given 18 hours before study. Superfusion with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 50 µmol/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 µm 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 µg per rat IP) significantly attenuated L-NAME–stimulated leukocyte rolling, to 12±2 (P<0.01); adherence, to 5±0.5 leukocytes per 100 µm (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.
Key Words: HMG-CoA reductase inhibitors • P-selectin • leukocyte rolling • leukocyte transmigration • nitric oxide
This article has been cited by other articles:
 |
|
 |
|
  V. Chopra and S. A. Flanders Does Statin Use Improve Pneumonia Outcomes? Chest, November 1, 2009; 136(5): 1381 - 1388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Reis, Xiaoyu Tan, Rongjie Yang, C. E. Rockwell, C. J. Papasian, S. N. Vogel, D. C. Morrison, A. A. Qureshi, and N. Qureshi A combination of proteasome inhibitors and antibiotics prevents lethality in a septic shock model Innate Immunity, October 1, 2008; 14(5): 319 - 329. [Abstract] [PDF]
|
|
|
|
 |
|
 E Hothersall, C McSharry, and N C Thomson Potential therapeutic role for statins in respiratory disease. Thorax, August 1, 2006; 61(8): 729 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Yamakuchi, J. J.M. Greer, S. J. Cameron, K. Matsushita, C. N. Morrell, K. Talbot-Fox, W. M. Baldwin III, D. J. Lefer, and C. J. Lowenstein HMG-CoA Reductase Inhibitors Inhibit Endothelial Exocytosis and Decrease Myocardial Infarct Size Circ. Res., June 10, 2005; 96(11): 1185 - 1192. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Fessler, S. K. Young, S. Jeyaseelan, J. G. Lieber, P. G. Arndt, J. A. Nick, and G. S. Worthen A Role for Hydroxy-Methylglutaryl Coenzyme A Reductase in Pulmonary Inflammation and Host Defense Am. J. Respir. Crit. Care Med., March 15, 2005; 171(6): 606 - 615. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Miyahara, J. Kiryu, K. Yamashiro, K. Miyamoto, F. Hirose, H. Tamura, H. Katsuta, K. Nishijima, A. Tsujikawa, and Y. Honda Simvastatin Inhibits Leukocyte Accumulation and Vascular Permeability in the Retinas of Rats with Streptozotocin-Induced Diabetes Am. J. Pathol., May 1, 2004; 164(5): 1697 - 1706. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Tailor, D. J. Lefer, and D. N. Granger HMG-CoA reductase inhibitor attenuates platelet adhesion in intestinal venules of hypercholesterolemic mice Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1402 - H1407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Galinanes and A. G Fowler Role of clinical pathologies in myocardial injury following ischaemia and reperfusion Cardiovasc Res, February 15, 2004; 61(3): 512 - 521. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Pierre-Paul and V. Gahtan Noncholesterol-Lowering Effects of Statins Vascular and Endovascular Surgery, September 1, 2003; 37(5): 301 - 313. [Abstract] [PDF]
|
|
|
|
 |
|
 W. Balduini, E. Mazzoni, S. Carloni, M. G. De Simoni, C. Perego, L. Sironi, and M. Cimino Prophylactic but Not Delayed Administration of Simvastatin Protects Against Long-Lasting Cognitive and Morphological Consequences of Neonatal Hypoxic-Ischemic Brain Injury, Reduces Interleukin-1{beta} and Tumor Necrosis Factor-{alpha} mRNA Induction, and Does Not Affect Endothelial Nitric Oxide Synthase Expression Stroke, August 1, 2003; 34(8): 2007 - 2012. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Chello, P Mastroroberto, G Patti, A D'Ambrosio, M C. Morichetti, G Di Sciascio, and E Covino Simvastatin attenuates leucocyte-endothelial interactions after coronary revascularisation with cardiopulmonary bypass Heart, May 1, 2003; 89(5): 538 - 543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Rezaie-Majd, G. W. Prager, R. A. Bucek, G. H. Schernthaner, T. Maca, H.-G. Kress, P. Valent, B. R. Binder, E. Minar, and M. Baghestanian Simvastatin Reduces the Expression of Adhesion Molecules in Circulating Monocytes From Hypercholesterolemic Patients Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 397 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Pruefer, J. Makowski, M. Dahm, S. Guth, H. Oelert, H. Darius, and M. Buerke Aprotinin inhibits leukocyte-endothelial cell interactions after hemorrhage and reperfusion Ann. Thorac. Surg., January 1, 2003; 75(1): 210 - 215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Dichtl, J. Dulak, M. Frick, H. F. Alber, S. P. Schwarzacher, M. P.S. Ares, J. Nilsson, O. Pachinger, and F. Weidinger HMG-CoA Reductase Inhibitors Regulate Inflammatory Transcription Factors in Human Endothelial and Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 58 - 63. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kawashima, T. Yamashita, Y. Miwa, M. Ozaki, M. Namiki, T. Hirase, N. Inoue, K.-i. Hirata, and M. Yokoyama HMG-CoA Reductase Inhibitor Has Protective Effects Against Stroke Events in Stroke-Prone Spontaneously Hypertensive Rats Stroke, January 1, 2003; 34(1): 157 - 163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Hernandez-Presa, M. Ortego, J. Tunon, J. L. Martin-Ventura, S. Mas, L. M. Blanco-Colio, C. Aparicio, L. Ortega, J. Gomez-Gerique, F. Vivanco, et al. Simvastatin reduces NF-{kappa}B activity in peripheral mononuclear and in plaque cells of rabbit atheroma more markedly than lipid lowering diet Cardiovasc Res, January 1, 2003; 57(1): 168 - 177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Honjo, H. Tanihara, K. Nishijima, J. Kiryu, Y. Honda, B. Y. J. T. Yue, and T. Sawamura Statin Inhibits Leukocyte-Endothelial Interaction and Prevents Neuronal Death Induced by Ischemia-Reperfusion Injury in the Rat Retina Arch Ophthalmol, December 1, 2002; 120(12): 1707 - 1713. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Mason, Z. Ahmed, R. Mankoff, E. A. Lidington, S. Ahmad, V. Bhatia, A. Kinderlerer, A. M. Randi, and D. O. Haskard Statin-Induced Expression of Decay-Accelerating Factor Protects Vascular Endothelium Against Complement-Mediated Injury Circ. Res., October 18, 2002; 91(8): 696 - 703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Lefer Statins as Potent Antiinflammatory Drugs Circulation, October 15, 2002; 106(16): 2041 - 2042. [Full Text] [PDF]
|
|
|
|
|
|
D. Pruefer, J. Makowski, M. Schnell, U. Buerke, M. Dahm, H. Oelert, U. Sibelius, U. Grandel, F. Grimminger, W. Seeger, et al. Simvastatin Inhibits Inflammatory Properties of Staphylococcus aureus{alpha}-Toxin Circulation, October 15, 2002; 106(16): 2104 - 2110. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Neuhaus, S. Strasser-Fuchs, F. Fazekas, B.C. Kieseier, G. Niederwieser, H.P. Hartung, and J.J. Archelos Statins as immunomodulators: Comparison with interferon-{beta}1b in MS Neurology, October 8, 2002; 59(7): 990 - 997. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. C. Kaneider, P. Egger, S. Dunzendorfer, and C. J. Wiedermann Rho-GTPase-Dependent Platelet-Neutrophil Interaction Affected by HMG-CoA Reductase Inhibition With Altered Adenosine Nucleotide Release and Function Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 1029 - 1035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Loftus and M. Thompson The role of matrix metalloproteinases in vascular disease Vascular Medicine, May 1, 2002; 7(2): 117 - 133. [Abstract] [PDF]
|
|
|
|
|
|
C. Urbich, E. Dernbach, A. M. Zeiher, and S. Dimmeler Double-Edged Role of Statins in Angiogenesis Signaling Circ. Res., April 5, 2002; 90(6): 737 - 744. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. I. McFarlane, R. Muniyappa, R. Francisco, and J. R. Sowers Pleiotropic Effects of Statins: Lipid Reduction and Beyond J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1451 - 1458. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ikeda, L. H. Young, and A. M. Lefer Attenuation of neutrophil-mediated myocardial ischemia-reperfusion injury by a calpain inhibitor Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1421 - H1426. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. E. Ferrier, M. H. Muhlmann, J.-P. Baguet, J. D. Cameron, G. L. Jennings, A. M. Dart, and B. A. Kingwell Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension J. Am. Coll. Cardiol., March 20, 2002; 39(6): 1020 - 1025. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Jones, S. D. Trocha, and D. J. Lefer Pretreatment With Simvastatin Attenuates Myocardial Dysfunction After Ischemia and Chronic Reperfusion Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 2059 - 2064. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Balduini, V. De Angelis, E. Mazzoni, and M. Cimino Simvastatin Protects Against Long-Lasting Behavioral and Morphological Consequences of Neonatal Hypoxic/Ischemic Brain Injury Stroke, September 1, 2001; 32(9): 2185 - 2191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Yoshida, T. Sawada, H. Ishii, R. E. Gerszten, A. Rosenzweig, M. A. Gimbrone Jr, Y. Yasukochi, and F. Numano HMG-CoA Reductase Inhibitor Modulates Monocyte-Endothelial Cell Interaction Under Physiological Flow Conditions In Vitro : Involvement of Rho GTPase-Dependent Mechanism Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1165 - 1171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Scalia, M. E. Gooszen, S. P. Jones, M. Hoffmeyer, D. M. Rimmer III, S. D. Trocha, P. L. Huang, M. B. Smith, A. M. Lefer, and D. J. Lefer Simvastatin Exerts Both Anti-inflammatory and Cardioprotective Effects in Apolipoprotein E-Deficient Mice Circulation, May 29, 2001; 103(21): 2598 - 2603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. van Nieuw Amerongen and V. W.M. van Hinsbergh Cytoskeletal Effects of Rho-Like Small Guanine Nucleotide-Binding Proteins in the Vascular System Arterioscler Thromb Vasc Biol, March 1, 2001; 21(3): 300 - 311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M Lefer, R. Scalia, and D. J Lefer Vascular effects of HMG CoA-reductase inhibitors (statins) unrelated to cholesterol lowering: new concepts for cardiovascular disease Cardiovasc Res, February 1, 2001; 49(2): 281 - 287. [Full Text] [PDF]
|
|
|
|
|
|
U. Laufs, M. Endres, F. Custodis, K. Gertz, G. Nickenig, J. K. Liao, and M. Bohm Suppression of Endothelial Nitric Oxide Production After Withdrawal of Statin Treatment Is Mediated by Negative Feedback Regulation of Rho GTPase Gene Transcription Circulation, December 19, 2000; 102(25): 3104 - 3110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. v. N. Amerongen, M. A. Vermeer, P. Negre-Aminou, J. Lankelma, J. J. Emeis, and V. W. M. van Hinsbergh Simvastatin Improves Disturbed Endothelial Barrier Function Circulation, December 5, 2000; 102(23): 2803 - 2809. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Laufs and J. K. Liao Targeting Rho in Cardiovascular Disease Circ. Res., September 29, 2000; 87(7): 526 - 528. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ando, T. Takamura, T. Ota, Y. Nagai, and K.-i. Kobayashi Cerivastatin Improves Survival of Mice with Lipopolysaccharide-Induced Sepsis J. Pharmacol. Exp. Ther., September 1, 2000; 294(3): 1043 - 1046. [Abstract] [Full Text]
|
|
|
|
|
|
W. Ni, K. Egashira, C. Kataoka, S. Kitamoto, M. Koyanagi, S. Inoue, and A. Takeshita Antiinflammatory and Antiarteriosclerotic Actions of HMG-CoA Reductase Inhibitors in a Rat Model of Chronic Inhibition of Nitric Oxide Synthesis Circ. Res., August 31, 2001; 89(5): 415 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Hayashidani, H. Tsutsui, T. Shiomi, N. Suematsu, S. Kinugawa, T. Ide, J. Wen, and A. Takeshita Fluvastatin, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, Attenuates Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction Circulation, February 19, 2002; 105(7): 868 - 873. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Urbich, E. Dernbach, A. M. Zeiher, and S. Dimmeler Double-Edged Role of Statins in Angiogenesis Signaling Circ. Res., April 5, 2002; 90(6): 737 - 744. [Abstract] [Full Text] [PDF]
|
|