The effect of vitamin E, probucol, and lovastatin on oxidative status and aortic fatty lesions in hyperlipidemic-diabetic hamsters.
Diabetes mellitus is associated with an increased risk of premature atherosclerosis, which may be due in part to an increased rate of low density lipoprotein (LDL) oxidation. Previous studies have shown that vitamin E, probucol, and lovastatin can reduce the oxidative susceptibility of LDL in normoglycemic animal models; however, few studies have investigated this in conjunction with aortic fatty streak lesion formation in diabetic hyperlipidemic models. Forty-eight Syrian hamsters were made diabetic by intraperitoneal injection of low dose streptozotocin. Diabetic animals (12 animals/groups) received a high saturated fat and cholesterol diet for 12.5 weeks. At 2.5 week of dietary treatments, the diet was supplemented with either: (1) 500 IU/day vitamin E (D+E); (2) 1% probucol w/w of the diet (D+P); (3) 25 mg/kg lovastatin (D+L); or (4) diabetic control (D). An age-matched group of hamsters (n=6) receiving the same diet but not made diabetic (ND) was used as control. At the end of the study, aortic arch foam cell-rich fatty streak lesion, plasma glucose, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides (TG), phospholipids, alpha-tocopherol, plasma lipid peroxide and the susceptibility of LDL to copper-catalyzed oxidation were determined. Diabetes increased plasma glucose, and when combined with an atherogenic diet resulted in a further increase of plasma lipids. Vitamin E, probucol, and lovastatin significantly reduced plasma TG in the diabetic hamsters fed the atherogenic diet. Vitamin E treatment increased TC, probucol reduced HDL-C without affecting TC; whereas lovastatin reduced TC and selectively decreased non-HDL-C, and significantly reduced fatty streak lesion formation in the aortic arch. While vitamin E and probucol were effective in reducing several indices of oxidative stress including plasma lipid peroxides, cholesterol oxidation products and in vitro LDL oxidation, they had no effect on fatty streak lesion formation. Our results indicate that the LDL in diabetic animals is more susceptible to oxidation than in non-diabetic hamsters and that not only vitamin E and probucol but also lovastatin provide antioxidant protection. It appears that in this combined model of diabetes and hypercholesterolemia, progression of fatty streak lesion formation is mainly associated with changes in TC and non-HDL-C as affected by lovastatin, and is less dependent on the extent of LDL oxidation, changes in plasma TG level and oxidative stress status.
El-Swefy
S
S
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Vascular Biology Laboratory, 711 Washington Street, Boston, MA 02111, USA.
Schaefer
E J
EJ
Seman
L J
LJ
van Dongen
D
D
Sevanian
A
A
Smith
D E
DE
Ordovas
J M
JM
El-Sweidy
M
M
Meydani
M
M
D000818:Animals; D000831:Animals, Newborn; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000032:analysis / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D006224:Cricetinae; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy; D004195:Disease Models, Animal; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy*; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000502:physiology; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D011341:Probucol / Q000494:pharmacology*; D012016:Reference Values; D013311:Streptozocin; D014810:Vitamin E / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D000975:Antioxidants; D014810:Vitamin E; D013311:Streptozocin; D008148:Lovastatin; D011341:Probucol