Effects of simvastatin treatment on oxidant/antioxidant state and ultrastructure of diabetic rat myocardium.

In the present study we investigated the effects of simvastatin treatment on lipid metabolism and peroxidation, antioxidant enzyme activities and ultrastructure of the diabetic rat myocardium. Diabetes was induced by single injection of streptozotocin (45 mg/kg i.p.). Eight weeks after induction of diabetes, a subgroup of control and of diabetic rats was treated with simvastatin for 4 weeks (10 mg/kg/day, orally). Blood glucose, plasma cholesterol and triacylglycerol, as well as levels of cardiac thiobarbituric acid reactive substances (TBARS) were significantly increased in diabetic rats. The activities of antioxidant enzymes, catalase (CAT) and glutathione peroxidase (GSHPx), were also elevated in the diabetic myocardium. Treatment with simvastatin markedly reduced serum triacylglycerol and cholesterol, and partially controlled hyperglycemia in diabetic animals. The increased activation of antioxidant enzymes and the excess of lipid peroxidation measured by TBARS were completely reversed by simvastatin treatment. Diabetic rats displayed ultrastructural ischemia-like alterations of cardiomyocytes and capillaries, which support oxidative stress-induced tissue remodelling. In the diabetic myocardium simvastatin treatment partly attenuated angiopathic and atherogenic processes, detected by electron microscopy. These results suggest that simvastatin, known as a lipid-lowering drug, may positively affect diabetes induced cardiovascular complications via reducing risks of atherosclerotic pathological processes, such as imbalance between oxidant and antioxidant state.

Ceylan A ，Karasu C ，Aktan F ，Güven C ，Can B ，Ozansoy G ... -  《GENERAL PHYSIOLOGY AND BIOPHYSICS》

Effects of simvastatin treatment on oxidant/antioxidant state and ultrastructure of streptozotocin-diabetic rat lung.

In the present study, we investigated the effects of simvastatin, a 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, on lipid metabolism, lipid peroxidation, antioxidant enzyme activities and ultrastructure of diabetic rat lung. Diabetes was induced by a single injection of streptozotocin (45 mg kg(-1), i.p.). After 8 weeks induction of diabetes, some control and diabetic rats were treated with simvastatin (10 mg kg(-1) rat day(-1); orally) for 4 weeks. Diabetes resulted in significantly high levels of blood glucose and plasma lipids. Malondialdehyde levels were unchanged after 12-week-old diabetic rats, whereas catalase activity significantly decreased in the lung. Glutathione peroxidase activity and nitric oxide level were significantly elevated in the diabetic lung. Histological analysis of the diabetic lung revealed some deterioration in the structure. Simvastatin treatment reduced plasma lipid levels and partially decreased the severity of hyperglycaemia. Catalase, glutathione peroxidase activities and nitric oxide levels were partially restored and accompanied by improved structure in diabetic lung by the simvastatin treatment. These results suggest that structural disturbances and alteration of antioxidative enzyme activities occurred in diabetic lung. Simvastatin treatment may provide some benefits in the maintenance of antioxidant status and structural organization of diabetes-induced injury of lung.

Ozansoy G ，Güven C ，Ceylan A ，Can B ，Aktan F ，Oz E ，Gönül B ... -  《CELL BIOCHEMISTRY AND FUNCTION》

Effects of vitamin A and insulin on the antioxidative state of diabetic rat heart: a comparison study with combination treatment.

Because elevated oxidative stress may exacerbate cardiovascular complications of diabetes mellitus, the current study aimed to investigate the effects of treatment with either vitamin A, an antioxidant, or with insulin on lipid peroxidation products and antioxidant enzyme activities of diabetic rat heart. Also to evaluate whether a combination of vitamin A and insulin exerts more beneficial effects than treatment with each agent alone. Rats were made diabetic with a single injection of streptozotocin (STZ, 55 mg kg(-1) i.p.). Two days after STZ-injection, one group of diabetic rats was treated with vitamin A (retinol acetate, 30 mg kg(-1) day(-1) i.o.) for 12 weeks. A second group of diabetic rats was untreated for 6 weeks and then treated for another 6 weeks with insulin (8-10 IU rat(-1) day(-1) s.c.). Both therapies were applied to another group of diabetic rats for assessment of combined therapy with vitamin A plus insulin. Hearts from 12-week untreated diabetic animals showed about a four-fold increase in the level of thiobarbituric acid reactive substances (TBARS), indicative of increased lipid peroxidation. This was accompanied by approximately 100% increase in both catalase and glutathione peroxidase (GSHPx) enzyme activities. Therapy with insulin alone caused a small but significant improvement in plasma TBARS as well as GSHPx activities, but no significant change in plasma catalase in diabetic animals. Diabetes-induced disturbance in TBARS was almost completely prevented by vitamin A therapy. Although, a similar degree of activities for GSHPx was determined in diabetic animals treated with each agent alone, combination therapy was found to be more effective than single therapies in the recovery of GSHPx of diabetic heart. In contrast to insulin single therapy, vitamin A alone significantly prevented an increase in catalase activity of diabetic heart, and a combination of these agents did not supply any further benefit. Superoxide dismutase (SOD) activity was not found significantly different among the experimental groups. STZ-diabetes also resulted in less plasma retinol and retinol-binding protein (RBP), which was significantly improved by insulin single therapy while vitamin A used alone, failed to increase plasma retinol and RBP levels of diabetic animals. Our findings suggest that single therapy with insulin is unable to preclude oxidative reactions in diabetic heart to the same extent as obtained by vitamin A therapy alone, in spite of allowing recovery of normal growth rate and improved vitamin A metabolism in diabetic rats. A combination of insulin with vitamin A may provide more benefits than use of either agent alone in the treatment of general characteristics of diabetes and the maintenance of antioxidant defence of diabetic heart and thus in the reduction of peroxidative stress-induced cardiac injury.

Zobali F ，Avci A ，Canbolat O ，Karasu C ... -  《CELL BIOCHEMISTRY AND FUNCTION》

Effects of cod liver oil on tissue antioxidant pathways in normal and streptozotocin-diabetic rats.

Lipid disorders and increased oxidative stress may exacerbate some complications of diabetes mellitus. Previous studies have implicated the beneficial effects of some antioxidants, omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the protection of cells from the destructive effect of increased lipids and lipid peroxidation products. This study, therefore, was designed to investigate the effects of cod liver oil (CLO, Lysi Ltd. Island), which comprises mainly vitamin A, PUFAs, EPA and DHA. Effects were monitored on plasma lipids, lipid peroxidation products (MDA) and the activities of antioxidant enzymes, glutathione peroxidase (GSHPx) and catalase in heart, liver, kidney and lung of non-diabetic control and streptozotocin (STZ)-induced-diabetic rats. Two days after STZ-injection (55 mg kg(-1) i.p.), non-diabetic control and diabetic rats were divided randomly into two groups as untreated or treated with CLO (0.5 ml kg(-1) rat per day) for 12 weeks. Plasma glucose, triacylglycerol and cholesterol concentrations were significantly elevated in 12-week untreated-diabetic animals; CLO treatment almost completely prevented these abnormalities in triacylglycerol and cholesterol, but hyperglycaemia was partially controlled. CLO also provided better weight gain in diabetic animals. In untreated diabetic rats, MDA markedly increased in aorta, heart and liver but was not significantly changed in kidney and lung. This was accompanied by a significant increase in both GSHPx and catalase enzyme activities in aorta, heart, and liver of diabetic rats. In kidney and lung, diabetes resulted in reduced catalase while GSHPx was significantly activated. In aorta, heart, and liver, diabetes-induced changes in MDA were entirely prevented by CLO treatment. In the tissues of CLO-treated diabetic animals, GSHPx activity paralleled those of control animals. CLO treatment also caused significant improvements in catalase activities in every tissue of diabetic rats, but failed to affect MDA and antioxidant activity in control animals. The current study suggests that the treatment of diabetic rats with CLO provides better control of glucose and lipid metabolism, allows recovery of normal growth rate, prevents oxidative/peroxidative stress and ameliorates endogenous antioxidant enzyme activities in various tissues. Because CLO contains a plethora of beneficial compounds together, its use for the management of diabetes-induced complications may provide important advantages.

Hünkar T ，Aktan F ，Ceylan A ，Karasu C ，Antioxidants in Diabetes-Induced Complications (ADIC) Study Group ... -  《CELL BIOCHEMISTRY AND FUNCTION》

Simvastatin treatment restores vasoconstriction and the inhibitory effect of LPC on endothelial relaxation via affecting oxidizing metabolism in diabetic rats.

Oxidative stress and dyslipidaemia play an important role in the development of diabetes-induced vascular complications. The aim of this study was to examine the reversal effects of simvastatin on some metabolic and oxidative parameters, and vascular functions in diabetic rats. Diabetes was induced by a single injection of streptozotocin (STZ, 45 mg/kg, i.p.). Eight weeks after STZ induction, some of the diabetic and control rats were treated with simvastatin (10 mg/kg rat/d) for 4 weeks. Plasma glucose, triglyceride and total cholesterol concentrations were significantly increased in 12-week diabetic rats. Simvastatin treatment stopped the loss of body weight, completely normalized the increase of plasma lipids and partially reduced the hyperglycaemia in diabetic rats. Increased malondialdehyde levels, catalase and glutathione peroxidase activities were normalised by simvastatin treatment in diabetic aorta. Phenylephrine (PE)-induced contractility in aorta rings was unaffected by diabetes, but was markedly decreased after simvastatin treatment in both control and diabetic rats. Reduction of endothelium-dependent vasorelaxation in diabetes was significantly ameliorated by simvastatin treatment. Incubation of aorta rings with lysophosphatidylcholine, a component of the oxidized LDL, did not significantly affect PE-induced contractions, but reduced endothelium-dependent relaxations more in untreated-diabetic rats than in other experimental groups. The endothelium-independent vasorelaxations were similar in all ring preparations. These results indicate that simvastatin treatment may ameliorate diabetes-induced abnormal vasoconstriction and endothelial dysfunction via affecting general and oxidizing metabolism, nitric oxide disability and intracellular calcium mobilisation.

Ceylan A ，Karasu C ，Aktan F ，Ozansoy G ... -  《diabetes nutrition & metabolism》