HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia

Institut fur Prophylaxe der Kreislaufkrankheiten, Ludwig-Maximilians-Universitat, Munich, Germany.

OBJECTIVES: This study sought to determine whether inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase affect CD11b expression and adhesiveness of monocytes in vitro and after treatment of patients with hypercholesterolemia. BACKGROUND: HMG-CoA reductase inhibitors improve survival of patients with coronary heart disease (CHD) and prevent CHD in hypercholesterolemic men. Because these drugs have been shown to modulate monocyte functions, they may act by reducing monocyte adhesion to endothelium, which is crucial in atherogenesis. METHODS: Isolated human blood monocytes were subjected to flow cytometric detection of CD11b and adhesion assays on fixed human endothelial cells after treatment with lovastatin in vitro or ex vivo before and after treatment of hypercholesterolemic patients with HMG-CoA reductase inhibitors. RESULTS: The integrin heterodimer CD11b/CD18 expressed on monocytes interacts with intercellular adhesion molecule-1 on endothelium and is involved in monocyte adhesion to endothelium. Treatment of monocytes with lovastatin in vitro slightly and dose dependently reduced surface expression of CD11b on monocytes. Moreover, lovastatin inhibited CD11b-dependent adhesiveness to fixed endothelium of unstimulated monocytes or monocytes stimulated with monocyte chemotactic protein 1. Coincubation with mevalonate, but not with low density lipoprotein (LDL), reversed the effects of lovastatin, suggesting that early cholesterol precursors, but not cholesterol, are crucial for adhesiveness of CD11b. In hypercholesterolemic patients, adhesion of isolated monocytes to endothelium ex vivo was dramatically increased over values in healthy control subjects. Treatment of these patients with the HMG-CoA reductase inhibitors lovastatin or simvastatin (20 to 40 mg/day) for 6 weeks slightly decreased total and LDL cholesterol plasma levels and monocyte CD11b surface expression but resulted in a significant reduction of monocyte adhesion to endothelium (p < 0.01, n = 7). CONCLUSIONS: The reduction of CD11b expression and inhibition of CD11b-dependent monocyte adhesion to endothelium may crucially contribute to the clinical benefit of HMG-CoA reductase inhibitors in CHD, independent of cholesterol-lowering effects.

This article has been cited by other articles:

				A. Alipour, A. J.H. H.M van Oostrom, A. Izraeljan, C. Verseyden, J. M. Collins, K. N. Frayn, T. W.M. Plokker, J. W. F. Elte, and M. Castro Cabezas Leukocyte Activation by Triglyceride-Rich Lipoproteins Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 792 - 797. [Abstract] [Full Text] [PDF]

				F. Gao, L. Linhartova, A. McD. Johnston, and D. R. Thickett Statins and sepsis Br. J. Anaesth., March 1, 2008; 100(3): 288 - 298. [Abstract] [Full Text] [PDF]

				P. Ferdinandy, R. Schulz, and G. F. Baxter Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning Pharmacol. Rev., December 1, 2007; 59(4): 418 - 458. [Abstract] [Full Text] [PDF]

				M.W. Merx and C. Weber Sepsis and the Heart Circulation, August 14, 2007; 116(7): 793 - 802. [Abstract] [Full Text] [PDF]

				K. Yamada, E. Sakurai, M. Itaya, S. Yamasaki, and Y. Ogura Inhibition of Laser-Induced Choroidal Neovascularization by Atorvastatin by Downregulation of Monocyte Chemotactic Protein-1 Synthesis in Mice Invest. Ophthalmol. Vis. Sci., April 1, 2007; 48(4): 1839 - 1843. [Abstract] [Full Text] [PDF]

				G. Patti, M. Chello, V. Pasceri, D. Colonna, A. Nusca, M. Miglionico, A. D'Ambrosio, E. Covino, and G. Di Sciascio Protection From Procedural Myocardial Injury by Atorvastatin Is Associated With Lower Levels of Adhesion Molecules After Percutaneous Coronary Intervention: Results From the ARMYDA-CAMs (Atorvastatin for Reduction of MYocardial Damage during Angioplasty-Cell Adhesion Molecules) Substudy J. Am. Coll. Cardiol., October 17, 2006; 48(8): 1560 - 1566. [Abstract] [Full Text] [PDF]

				B. Chandrasekar, S. Mummidi, L. Mahimainathan, D. N. Patel, S. R. Bailey, S. Z. Imam, W. C. Greene, and A. J. Valente Interleukin-18-induced Human Coronary Artery Smooth Muscle Cell Migration Is Dependent on NF-{kappa}B- and AP-1-mediated Matrix Metalloproteinase-9 Expression and Is Inhibited by Atorvastatin J. Biol. Chem., June 2, 2006; 281(22): 15099 - 15109. [Abstract] [Full Text] [PDF]

				H. J. Zambarakji, T. Nakazawa, E. Connolly, A. M. Lane, S. Mallemadugula, M. Kaplan, N. Michaud, A. Hafezi-Moghadam, E. S. Gragoudas, and J. W. Miller Dose-dependent effect of pitavastatin on VEGF and angiogenesis in a mouse model of choroidal neovascularization. Invest. Ophthalmol. Vis. Sci., June 1, 2006; 47(6): 2623 - 2631. [Abstract] [Full Text] [PDF]

				A. Kawakami, M. Aikawa, P. Libby, P. Alcaide, F. W. Luscinskas, and F. M. Sacks Apolipoprotein CIII in Apolipoprotein B Lipoproteins Enhances the Adhesion of Human Monocytic Cells to Endothelial Cells Circulation, February 7, 2006; 113(5): 691 - 700. [Abstract] [Full Text] [PDF]

				O. Quehenberger Thematic Review Series: The Immune System and Atherogenesis. Molecular mechanisms regulating monocyte recruitment in atherosclerosis J. Lipid Res., August 1, 2005; 46(8): 1582 - 1590. [Abstract] [Full Text] [PDF]

				M. W. Merx, E. A. Liehn, J. Graf, A. van de Sandt, M. Schaltenbrand, J. Schrader, P. Hanrath, and C. Weber Statin Treatment After Onset of Sepsis in a Murine Model Improves Survival Circulation, July 5, 2005; 112(1): 117 - 124. [Abstract] [Full Text] [PDF]

				O. L. Francone, L. Royer, G. Boucher, M. Haghpassand, A. Freeman, D. Brees, and R. J. Aiello Increased Cholesterol Deposition, Expression of Scavenger Receptors, and Response to Chemotactic Factors in Abca1-Deficient Macrophages Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1198 - 1205. [Abstract] [Full Text] [PDF]

				J. Pleiner, G. Schaller, F. Mittermayer, S. Zorn, C. Marsik, S. Polterauer, S. Kapiotis, and M. Wolzt Simvastatin Prevents Vascular Hyporeactivity During Inflammation Circulation, November 23, 2004; 110(21): 3349 - 3354. [Abstract] [Full Text] [PDF]

				M. W. Merx, E. A. Liehn, U. Janssens, R. Lutticken, J. Schrader, P. Hanrath, and C. Weber HMG-CoA Reductase Inhibitor Simvastatin Profoundly Improves Survival in a Murine Model of Sepsis Circulation, June 1, 2004; 109(21): 2560 - 2565. [Abstract] [Full Text] [PDF]

				U. Schonbeck and P. Libby Inflammation, Immunity, and HMG-CoA Reductase Inhibitors: Statins as Antiinflammatory Agents? Circulation, June 1, 2004; 109(21_suppl_1): II-18 - II-26. [Abstract] [Full Text] [PDF]

				J. Han, X. Zhou, T. Yokoyama, D. P. Hajjar, A. M. Gotto Jr, and A. C. Nicholson Pitavastatin Downregulates Expression of the Macrophage Type B Scavenger Receptor, CD36 Circulation, February 17, 2004; 109(6): 790 - 796. [Abstract] [Full Text] [PDF]

				M. M. Monick, L. S. Powers, N. S. Butler, and G. W. Hunninghake Inhibition of Rho Family GTPases Results in Increased TNF-{alpha} Production After Lipopolysaccharide Exposure J. Immunol., September 1, 2003; 171(5): 2625 - 2630. [Abstract] [Full Text] [PDF]

				Y. Almog Statins, Inflammation, and Sepsis: Hypothesis Chest, August 1, 2003; 124(2): 740 - 743. [Abstract] [Full Text] [PDF]

				K. H. Han, Y. Chen, M. K. Chang, Y. C. Han, J.-H. Park, S. R. Green, A. Boullier, and O. Quehenberger LDL activates signaling pathways leading to an increase in cytosolic free calcium and stimulation of CD11b expression in monocytes J. Lipid Res., July 1, 2003; 44(7): 1332 - 1340. [Abstract] [Full Text] [PDF]

				C. P. Tiefenbacher, J. Kapitza, V. Dietz, C.-H. Lee, and F. Niroomand Reduction of myocardial infarct size by fluvastatin Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H59 - H64. [Abstract] [Full Text] [PDF]

				H. L. Lazar, Y. Bao, Y. Zhang, and S. A. Bernard Pretreatment with statins enhances myocardial protection during coronary revascularization J. Thorac. Cardiovasc. Surg., May 1, 2003; 125(5): 1037 - 1042. [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]

				M. Sasaki, S. Bharwani, P. Jordan, T. Joh, K. Manas, A. Warren, H. Harada, P. Carter, J. W. Elrod, M. Wolcott, et al. The 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitor Pravastatin Reduces Disease Activity and Inflammation in Dextran-Sulfate Induced Colitis J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 78 - 85. [Abstract] [Full Text]

				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]

				Y. Majlesi, P. Samorapoompichit, A. W. Hauswirth, G.-H. Schernthaner, M. Ghannadan, M. Baghestanian, A. Rezaie-Majd, R. Valenta, W. R. Sperr, H.-J. Buhring, et al. Cerivastatin and atorvastatin inhibit IL-3-dependent differentiation and IgE-mediated histamine release in human basophils and downmodulate expression of the basophil-activation antigen CD203c/E-NPP3 J. Leukoc. Biol., January 1, 2003; 73(1): 107 - 117. [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]

				K. Stamatakis, E. Cernuda-Morollon, O. Hernandez-Perera, and D. Perez-Sala Isoprenylation of RhoB Is Necessary for Its Degradation. A NOVEL DETERMINANT IN THE COMPLEX REGULATION OF RhoB EXPRESSION BY THE MEVALONATE PATHWAY J. Biol. Chem., December 13, 2002; 277(51): 49389 - 49396. [Abstract] [Full Text] [PDF]

				P. Di Napoli, A.A. Taccardi, M. Oliver, and R. De Caterina Statins and stroke: evidence for cholesterol-independent effects Eur. Heart J., December 2, 2002; 23(24): 1908 - 1921. [PDF]

				M. F. Bellamy, P. A. Pellikka, K. W. Klarich, A. J. Tajik, and M. Enriquez-Sarano Association of cholesterol levels, hydroxymethylglutaryl coenzyme-a reductase inhibitor treatment, and progression of aortic stenosis in the community J. Am. Coll. Cardiol., November 20, 2002; 40(10): 1723 - 1730. [Abstract] [Full Text] [PDF]

				C. Stefanadis, K. Toutouzas, M. Vavuranakis, E. Tsiamis, D. Tousoulis, D.B. Panagiotakos, S. Vaina, C. Pitsavos, and P. Toutouzas Statin treatment is associated with reduced thermal heterogeneity in human atherosclerotic plaques Eur. Heart J., November 1, 2002; 23(21): 1664 - 1669. [Abstract] [Full Text] [PDF]

				W. Palinski and C. Napoli Unraveling Pleiotropic Effects of Statins on Plaque Rupture Arterioscler. Thromb. Vasc. Biol., November 1, 2002; 22(11): 1745 - 1750. [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]

				D. Li, H. Chen, F. Romeo, T. Sawamura, T. Saldeen, and J. L. Mehta Statins Modulate Oxidized Low-Density Lipoprotein-Mediated Adhesion Molecule Expression in Human Coronary Artery Endothelial Cells: Role of LOX-1 J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 601 - 605. [Abstract] [Full Text] [PDF]

				M.J. Sampson, I.R. Davies, J.C. Brown, K. Ivory, and D.A. Hughes Monocyte and Neutrophil Adhesion Molecule Expression During Acute Hyperglycemia and After Antioxidant Treatment in Type 2 Diabetes and Control Patients Arterioscler. Thromb. Vasc. Biol., July 1, 2002; 22(7): 1187 - 1193. [Abstract] [Full Text] [PDF]

				L. K. Newby, A. Kristinsson, M. V. Bhapkar, P. E. Aylward, A. P. Dimas, W. W. Klein, D. K. McGuire, D. J. Moliterno, F. W. A. Verheugt, W. D. Weaver, et al. Early Statin Initiation and Outcomes in Patients With Acute Coronary Syndromes JAMA, June 19, 2002; 287(23): 3087 - 3095. [Abstract] [Full Text] [PDF]

				E. Porreca, C. Di Febbo, G. Baccante, M. Di Nisio, and F. Cuccurullo Increased transforming growth factor-beta1 circulating levels and production in human monocytes after 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase inhibition with pravastatin J. Am. Coll. Cardiol., June 5, 2002; 39(11): 1752 - 1757. [Abstract] [Full Text] [PDF]

				W. Palinski and S. Tsimikas Immunomodulatory Effects of Statins: Mechanisms and Potential Impact on Arteriosclerosis J. Am. Soc. Nephrol., June 1, 2002; 13(6): 1673 - 1681. [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]

				R. Baetta, M. Camera, C. Comparato, C. Altana, M. D. Ezekowitz, and E. Tremoli Fluvastatin Reduces Tissue Factor Expression and Macrophage Accumulation in Carotid Lesions of Cholesterol-Fed Rabbits in the Absence of Lipid Lowering Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 692 - 698. [Abstract] [Full Text] [PDF]

				B. R. Kwak and F. Mach Statins Inhibit Leukocyte Recruitment: New Evidence for Their Anti-Inflammatory Properties Arterioscler. Thromb. Vasc. Biol., August 1, 2001; 21(8): 1256 - 1258. [Full Text] [PDF]

				R. Dechend, A. Fiebeler, J.-K. Park, D. N. Muller, J. Theuer, E. Mervaala, M. Bieringer, D. Gulba, R. Dietz, F. C. Luft, et al. Amelioration of Angiotensin II-Induced Cardiac Injury by a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor Circulation, July 31, 2001; 104(5): 576 - 581. [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]

				W. Palinsk New Evidence for Beneficial Effects of Statins Unrelated to Lipid Lowering Arterioscler. Thromb. Vasc. Biol., January 1, 2001; 21(1): 3 - 5. [Full Text] [PDF]

				C. P. Sparrow, C. A. Burton, M. Hernandez, S. Mundt, H. Hassing, S. Patel, R. Rosa, A. Hermanowski-Vosatka, P.-R. Wang, D. Zhang, et al. Simvastatin Has Anti-Inflammatory and Antiatherosclerotic Activities Independent of Plasma Cholesterol Lowering Arterioscler. Thromb. Vasc. Biol., January 1, 2001; 21(1): 115 - 121. [Abstract] [Full Text] [PDF]

				J. G. Wagner and R. A. Roth Neutrophil Migration Mechanisms, with an Emphasis on the Pulmonary Vasculature Pharmacol. Rev., September 1, 2000; 52(3): 349 - 374. [Abstract] [Full Text] [PDF]

				M. M. Sadeghi, M. Collinge, R. Pardi, and J. R. Bender Simvastatin Modulates Cytokine-Mediated Endothelial Cell Adhesion Molecule Induction: Involvement of an Inhibitory G Protein J. Immunol., September 1, 2000; 165(5): 2712 - 2718. [Abstract] [Full Text] [PDF]

				K. K. Koh Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability Cardiovasc Res, September 1, 2000; 47(4): 648 - 657. [Abstract] [Full Text] [PDF]

				D. Ferro, S. Parrotto, S. Basili, C. Alessandri, and F. Violi Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia J. Am. Coll. Cardiol., August 1, 2000; 36(2): 427 - 431. [Abstract] [Full Text] [PDF]

				W. B. Strawn, M. C. Chappell, R. H. Dean, S. Kivlighn, and C. M. Ferrario Inhibition of Early Atherogenesis by Losartan in Monkeys With Diet-Induced Hypercholesterolemia Circulation, April 4, 2000; 101(13): 1586 - 1593. [Abstract] [Full Text] [PDF]

				W. B Strawn, R. H Dean, and C. M Ferrario Novel mechanisms linking angiotensin II and early atherogenesis Journal of Renin-Angiotensin-Aldosterone System, March 1, 2000; 1(1): 11 - 17. [PDF]

				D. C. Hess, A. M. Demchuk, L. M. Brass, and F. M. Yatsu HMG-CoA reductase inhibitors (statins): A promising approach to stroke prevention Neurology, February 22, 2000; 54(4): 790 - 796. [Abstract] [Full Text] [PDF]

				C. J. Vaughan, A. M. Gotto Jr., and C. T. Basson The evolving role of statins in the management of atherosclerosis J. Am. Coll. Cardiol., January 1, 2000; 35(1): 1 - 10. [Abstract] [Full Text] [PDF]

				A. H. Wagner, T. Kohler, U. Ruckschloss, I. Just, and M. Hecker Improvement of Nitric Oxide-Dependent Vasodilatation by HMG-CoA Reductase Inhibitors Through Attenuation of Endothelial Superoxide Anion Formation Arterioscler. Thromb. Vasc. Biol., January 1, 2000; 20(1): 61 - 69. [Abstract] [Full Text] [PDF]

				D. Pruefer, R. Scalia, and A. M. Lefer Simvastatin Inhibits Leukocyte-Endothelial Cell Interactions and Protects Against Inflammatory Processes in Normocholesterolemic Rats Arterioscler. Thromb. Vasc. Biol., December 1, 1999; 19(12): 2894 - 2900. [Abstract] [Full Text] [PDF]

				L. Liu, P. Moesner, N. L. Kovach, R. Bailey, A. D. Hamilton, S. M. Sebti, and J. M. Harlan Integrin-dependent Leukocyte Adhesion Involves Geranylgeranylated Protein(s) J. Biol. Chem., November 19, 1999; 274(47): 33334 - 33340. [Abstract] [Full Text] [PDF]

				C. J. Vaughan and N. Delanty Neuroprotective Properties of Statins in Cerebral Ischemia and Stroke Stroke, September 1, 1999; 30(9): 1969 - 1973. [Abstract] [Full Text] [PDF]

				H. Drexler Nitric oxide and coronary endothelial dysfunction in humans Cardiovasc Res, August 15, 1999; 43(3): 572 - 579. [Full Text] [PDF]

				A. M. Lefer, B. Campbell, Y.-K. Shin, R. Scalia, R. Hayward, and D. J. Lefer Simvastatin Preserves the Ischemic-Reperfused Myocardium in Normocholesterolemic Rat Hearts Circulation, July 13, 1999; 100(2): 178 - 184. [Abstract] [Full Text] [PDF]

				K. H. Han, K. O. Han, S. R. Green, and O. Quehenberger Expression of the monocyte chemoattractant protein-1 receptor CCR2 is increased in hypercholesterolemia: differential effects of plasma lipoproteins on monocyte function J. Lipid Res., June 1, 1999; 40(6): 1053 - 1063. [Abstract] [Full Text]

				N. Hrboticky, G. Draude, G. Hapfelmeier, R. Lorenz, and P. C. Weber Lovastatin Decreases the Receptor-Mediated Degradation of Acetylated and Oxidized LDLs in Human Blood Monocytes During the Early Stage of Differentiation Into Macrophages Arterioscler. Thromb. Vasc. Biol., May 1, 1999; 19(5): 1267 - 1275. [Abstract] [Full Text] [PDF]