Inhibitors of Arterial Relaxation Among Components of Human Oxidized Low-Density Lipoproteins

Abstract

Background Oxidized low-density lipoproteins (LDLs) are known to impair arterial relaxation. The aim of the present study was to identify the components of oxidized LDL that may account for inhibition of endothelium-dependent relaxation. Methods and Results LDLs from 12 healthy subjects were either maintained at 4°C (native LDL) or incubated at 37°C in the presence of copper sulfate (oxidized LDL). Unlike pretreatment with native LDL, pretreatment with oxidized LDL reduced significantly the acetylcholine-mediated relaxation of rabbit aortic segments compared with control segments incubated in Krebs' buffer (maximal relaxation [E max ], 72.0±6.7% versus 94.1±0.8%, respectively, P <.01; negative logarithm of the concentration required to produce 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 (ΔE max ) correlated significantly with the formation of 7-ketocholesterol, 7α-hydroxycholesterol, and 7β-hydroxycholesterol. In contrast, ΔE max did not correlate with the amount of lipoperoxides or lysophosphatidylcholine formed, and the difference of pD 2 values measured with oxidized and native LDL (ΔpD 2 ) did not correlate significantly with any of the oxidation-derived LDL compounds. When added individually, 7-ketocholesterol and 7β-hydroxycholesterol reduced E max values but not pD 2 values in a time- and concentration-dependent manner. Conclusions Cholesterol derivatives in oxidized LDL can reduce maximal arterial relaxation through a specific effect on vascular endothelial cells.