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(Circulation. 1997;95:723-731.)
© 1997 American Heart Association, Inc.

Articles

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

Valerie Deckert, PhD; Laurence Persegol, PhD; Laurence Viens, MS; Gerard Lizard, PhD; Anne Athias, MS; Christian Lallemant, MD; Philippe Gambert, MD, PhD; Laurent Lagrost, PhD

the Laboratoire de Biochimie des Lipoproteines, INSERM CJF 93-10, Faculte de Medecine, Dijon, France.

Correspondence to Laurent Lagrost, Laboratoire de Biochimie Medicale, Hopital du Bocage, 21034 Dijon, France.

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 [pD₂], 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 (E_max) correlated significantly with the formation of 7-ketocholesterol, 7-hydroxycholesterol, and 7ß-hydroxycholesterol. In contrast, E_max did not correlate with the amount of lipoperoxides or lysophosphatidylcholine formed, and the difference of pD₂ values measured with oxidized and native LDL (pD₂) did not correlate significantly with any of the oxidation-derived LDL compounds. When added individually, 7-ketocholesterol and 7ß-hydroxycholesterol reduced E_max values but not pD₂ 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.

Key Words: lipoproteins • cholesterol • endothelium • acetylcholine • vessels

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