INHIBITORS OF ARTERIAL RELAXATION AMONG COMPONENTS OF HUMAN OXIDIZED LOW-DENSITY LIPOPROTEINS - CHOLESTEROL DERIVATIVES OXIDIZED IN POSITION-7 ARE POTENT INHIBITORS OF ENDOTHELIUM-DEPENDENT RELAXATION

Background Oxidized low-density lipoproteins (LDLs) are known to impai r arterial relaxation. The aim of the present study was to identify th e components of oxidized LDL that may account for inhibition of endoth elium-dependent relaxation. Methods and Results LDLs from 12 healthy s ubjects were either maintained at 4 degrees C (native LDL) or incubate d at 37 degrees C in the presence of copper sulfate (oxidized LDL). Un like pretreatment with native LDL, pretreatment with oxidized LDL redu ced significantly the acetylcholine-mediated relaxation of rabbit aort ic segments compared with control segments incubated in Krebs' buffer (maximal relaxation [E(max)], 72.0+/-6.7% versus 94.1+/-0.8%, respecti vely, P<.01; negative logarithm of the concentration required to produ ce a half-maximal relaxing effect [pD(2)], 6.6+/-0.1 versus 7.2+/-0.1, respectively, P<.001). The absolute difference between E(max) values obtained with oxidized and native LDL (Delta E(max)) correlated signif icantly with the formation of 7-ketocholesterol, 7 alpha-hydroxycholes terol, and 7 beta-hydroxycholesterol. in contrast, Delta E(max) did no t correlate with the amount of lipoperoxides or lysophosphatidylcholin e formed, and the difference of pD(2) values measured with oxidized an d native LDL (Delta pD(2)) did not correlate significantly with any of the oxidation-derived LDL compounds. When added individually, 7-ketoc holesterol and 7 beta-hydroxycholesterol reduced E(max) values but not pD(2) values in a time and concentration-dependent manner. Conclusion s Cholesterol derivatives in oxidized LDL can reduce maximal arterial relaxation through a specific effect on vascular endothelial cells.