Dietary oxysterols induce in vivo toxicity of coronary endothelial and smooth muscle cells.

Dietary cholesterol oxidation products (COPs) were reported to exhibit in vitro toxicity toward vascular cells. The aim of this study was to determine whether dietary COPs induce in vivo toxicity toward coronary arteries and to evaluate their effect on the coronary reactivity. Golden Syrian hamsters were fed either a normolipidic diet or a hyperlipidic diet with or without a mixture of COPs (1.4 mg/kg/day). At the end of the feeding periods, cardiac mitochondria and cytosol were prepared to determine the subcellular distribution of cytochrome c. Oxidative phosphorylation was evaluated with glutamate, pyruvate or palmitoylcarnitine as a substrate. The main coronary artery was examined all along its length by transmission electron microscopy (TEM). Plasma sterol concentrations were determined. Furthermore, at the end of the 3-month feeding period, the hearts were perfused at constant pressure by the Langendorff method. The endothelium-dependent reactivity to acetylcholine was evaluated. The myocardial sterol concentration was also estimated. After a 15-day diet with dietary COPs, a release of cytochrome c into the cytosolic fraction of the whole heart occurred, which indicated apoptosis of one or several types of cardiac cells probably induced by excess circulating cholestanetriol. The morphological data obtained by TEM after three months of diet suggested that mainly vascular cells (endothelial and smooth muscle cells) were damaged by dietary COPs, whereas cardiomyocytes appeared healthy. Furthermore, the mitochondrial oxidation of palmitoylcarnitine was reduced and that of pyruvate was increased, suggesting some maintenance of energy metabolism. This strengthens the hypothesis of apoptosis. Several changes in coronary reactivity suggesting an increased NO production were observed. In conclusion, dietary COPs triggered in vivo apoptosis of coronary cells through the release of cytochrome c in the cytosol. This toxicity was counterbalanced by an increased endothelium-dependent dilation.