INCREASED OXYSTEROL CONTENTS IN DIABETIC RAT HEARTS - THEIR INVOLVEMENT IN DIABETIC CARDIOMYOPATHY

BACKGROUND: Abnormal lipid metabolism associated with diabetes mellitu s has been proposed to be involved in the pathogenesis of diabetic car diomyopathy. Oxysterols, oxidation deriva tives of cholesterol, are kn own to be highly cytotoxic. OBJECTIVE: To monitor changes in myocardia l oxysterols and to assess the effect of probucol, a lipid lowering ag ent, on myocardial lipids and oxysterols in diabetic rats. METHODS AND RESULTS: Streptozotocin-induced diabetic rats were divided into two g roups; one group was put on a standard diet, and the other a diet cont aining 1% (weight/weight) probucol for eight weeks. Two oxysterols, 7 beta hydroxycholesterol and 7-ketocholesterol, were identified in myoc ardium by capillary gas chromatography. Both 7 beta-hydroxycholestero1 and 7-ketocholesterol were significantly increased in diabetic rats ( 49.9+/-9.4 ng/mg dry weight versus 5.8+/-1.2 in controls, P<0.05; and 5.3+/-1.2 ng/mg dry weight versus 1.7+/-0.1 in controls, P<0.01, respe ctively). Probucol reduced not only plasma lipids but also myocardial lipids except for cholesterol and sphingomyelin fractions. However, pr obucol did not improve insulin deficiency, glucose metabolism or myoca rdial oxysterol contents. CONCLUSIONS: This study demonstrated an incr ease in oxysterols in the myocardium of diabetic rats, suggesting that oxysterols may play a role in the development of diabetic cardiomyopa thy. Probucol did not decrease the myocardial oxysterol content at the dose used in this study, suggesting that the increase in oxysterols m ay not be attributed to high circulating concentrations of lipids, but rather to disturbed myocardial metabolism due to insulin deficiency.