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

Objectives. This study sought to determine whether inhibitors of 3-hyd roxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase affect CD11b exp ression and adhesiveness of monoytes in vitro and after treatment of p atients with hypercholesterolemia. Background. HMG-CoA reductase inhib itors improve survival of patients with coronary heart disease (CHD) a nd prevent CHD in hypercholesterolemic men. Because these drugs have b een shown to modulate monocyte functions, they may act by reducing mon ocyte adhesion to endothelium, which is crucial in atherogenesis. Meth ods. Isolated human blood monocytes were subjected to flow cytometric detection of CD11B and adhesion assays on fixed human endothelial cell s after treatment with lovastatin in vitro or ex vivo before and after treatment of hypercholesterolemic patients with HMG-CoA reductase inh ibitors. Results. The integrin heterodimer CD11b/CD18 expressed on mon ocytes interacts with intercellular adhesion molecule-1 on endothelium and is involved in monocyte adhesion to endothelium. Treatment of mon ocytes with lovastatin in vitro slightly and dose dependently reduced surface expression of CD11b on monocytes. Moreover, lovastatin inhibit ed CD11b dependent adhesiveness to fixed endothelium of unstimulated m onocytes or monocytes stimulated with monocyte chemotactic protein 1. Coincubation with mevalonate, but not with low density lipoprotein (LD L), reversed the effects of lovastatin, suggesting that early choleste rol precursors, but not cholesterol, are crucial for adhesiveness of C D11b. In hypercholesterolemic patients, adhesion of isolated monocytes to endothelium ex vivo was dramatically increased over values in heal thy control subjects, Treatment of these patients with the HMG-CoA red uctase inhibitors lovastatin or simvastatin (20 to 40 mg/day) for 6 we eks slightly decreased total and LDL cholesterol plasma levels and mon ocyte CD11b surface expression but resulted in a significant reduction of monocyte adhesion to endothelium (p < 0.01, n = 7). Conclusions. T he reduction of CD11b expression and inhibition of CD11b-dependent mon ocyte adhesion to endothelium may crucially contribute to the clinical benefit of HMG-CoA reductase inhibitors in CHID, independent of chole sterol-lowering effects. (C) 1997 by the American College of Cardiolog y.