الفهرس 
CONTENTSOnly 14 pages are availabe for public view
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Abstract
Background : Diabetic cardiomyopathy has become a major cause of DM-related morbidity and mortality. Sacubatril/valsartan is the first of a new class of drugs referred to as dual-acting angiotensin-receptor-neprilysin inhibitors that has been shown to reduce the morbidity and mortality of patients with heart failure. Glycophagy, a glycogen-specific autophagy, plays an important role in supplying the heart and liver with glucose under conditions of demand. The aim of the work: The present study was conducted to determine the added efficacy of sacubatril/valsartan, compared to valsartan alone, to prevent the development of DCM including its effects on cardiac GABARAPL1 gene expression (as a glycophagy marker) in high-fat diet/ low dose STZ- induced rat model of type 2 DM (T2DM). Materials and Methods: Forty Adult female Sprague-Dawley rats (8 weeks weighing 200- 220 g) were used in this study. Rats were randomly separated into 2 main groups: control group where rats were fed on a standard chow diet and diabetic groups where rats were fed a high-fat diet followed by injection of streptozotocin. Diabetic groups were maintained on HFD and further classified into three subgroups: untreated, valsartan-treated group and sacubatril/valsartan-treated group. After 12 week, body weight was measured and electrocardiography was recorded. Rats were scarified and their blood was collected for assay of fasting insulin level, Homeostasis model of assessment of insulin resistance and lipid profile. Hearts were rapidly excised and weighed. Further histopathological assessment of cardiac tissue samples were performed under light microscope. Transmission electron microscope was also used. Real-time polymerase chain reaction was used for assessment of GABARAPL1 mRNA gene expression in the heart samples. Results: DCM rat model was successfully established, evidenced by the development of marked hyperglycemia, dyslipidemia and insulin resistance associated with myocardial hypertrophy and fibrosis. Cardiomyocyte glycogen overload was observed, evidenced by impaired glycophagy process in diabetic hearts. Treatment of diabetic rats with valsartan resulted in lowering of FBG level and elevation of FI level. Also, valsartan therapy resulted in improvement of cholesterol and triglyceride levels. In addition, valsartan therapy was effective in preventing diabetes-associated cardiac hypertrophy and fibrosis. Furthermore, cardiac glycogen content was decreased by valsartan therapy.Treatment of diabetic rats with sacubatril/valsartan resulted in lowering of FBG level and elevation of FI level, with significant improvement of insulin sensitivity. Also, sacubatril/valsartan therapy resulted in improvement of all lipid profile parameters. In addition, sacubatril/valsartan therapy was more effective than valsartan in preventing diabetes-associated cardiac hypertrophy and fibrosis. Furthermore, cardiac glycogen content was markedly decreased by sacubatril/valsartan therapy, associated with induction of glycophagic activity in the diabetic hearts. Conclusion : Glycogen accumulation associated with a disruption in myocardial glycophagy, represents an important pathological determinant in the diabetic hearts. Sacubatril/valsartan therapy established a significant reduction of cardiac hypertrophy and fibrosis in rat model of DCM. These findings may be a result of direct cardioprotective effects or secondary to improved hyperglycemia and dyslipidemia. Induction of the myocardial glycophagy and alleviating cardiac glycogen overload might be one such mechanism. So, sacubatril/valsartan therapy provides a more favorable metabolic and cardioprotective response compared to valsartan alone in DCM rat model.