Effects of oxidized low density lipoprotein, lipid mediators and statins on vascular cell interactions

The integrin heterodimer CD11b/CD18 (alpha M beta 2, Mac-1, CR3) expressed on monocytes or polymorphonuclear leukocytes (PMN) is a receptor for iC3b, fibrinogen, heparin, and for intercellular adhesion molecule (ICAM)-1 on en dothelium, crucially contributing to vascular cell interactions in inflamma tion and atherosclerosis. In this report, we summarize our findings on the effects of lipid mediators and lipid-lowering drugs. Exposure of endothelia l cells to oxidized low density lipoprotein (oxLDL) induces upregulation of ICAM-1 and increases adhesion of monocytic cells expressing Mac-1. Inhibit ion experiments show that monocytes use distinct ligands, i.e. ICAM-1 and h eparan sulfate proteoglycans for adhesion to oxLDL-treated endothelium. An albumin-transferable oxLDL activity is inhibited by the antioxidant pyrroli dine dithiocarbamate (PDTC), while 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) or lysophosphatidylcholine had no effect, implicating yet unidentif ied radicals. Sequential adhesive! and signaling events lead to the firm ad hesion of rolling PMN on activated and adherent platelets, which may occupy areas of endothelial denudation. Shear resistant arrest of PMN on thrombin -stimulated platelets in flow conditions requires distinct regions of Mac-1 , involving its interactions with fibrinogen bound to platelet alpha llb be ta 3, and with other platelet ligands. Both arrest and adhesion strengtheni ng under flow are stimulated by platelet-activating factor and leukotriene B4, but not by the chemokine receptor CXCR2. We tested whether Mac-1-depend ent monocyte adhesiveness is affected by inhibitors of hydroxy-methylglutar yl-Coenzyme A reductase (statins) which improve morbidity and survival of p atients with coronary heart disease. As compared to controls, adhesion of i solated monocytes to endothelium ex vivo was increased in patients with hyp ercholesterolemia. Treatment with statins decreased total and low density l ipoprotein (LDL) cholesterol plasma levels, surface expression of Mac-1, an d resulted in a dramatic reduction of Mac,mediated monocyte adhesion to end othelium. The inhibition of monocyte adhesion was reversed by mevalonate bu t not LDL in vitro,indicating that isoprenoid precursors are crucial for ad hesiveness of Mac-1. Such effects may crucially contribute to the clinical benefit of statins, independent of cholesterol-lowering, and may represent a paradigm for novel, anti-inflammatory mechanisms of action by this class of drugs.