| Summary: | 碩士 === 高雄醫學大學 === 醫學系藥理學科碩士班 === 103 === Diabetes cardiomyopathy, a common disease occurring hypertension, hyperglycemia and ventricle hypertrophy in diabetes patients, is a major complication leads to heart failure. Recently, studies have reported that diabetes induced cardiomyocyte apoptosis and suppressed cardiac autophagy, showing that the relationship between the autophagy and apoptotic cell death pathways plays an important role in the pathogenesis of diabetic cardiomyopathy. Our recent studies indicated that KMUP-3 can induce autophagy in cardiomyocytes. Therefore, we further investigated whether KMUP-3’s promotion of autophagy activity can prevent high glucose (HG)-induce cardiac injury and improve cardiac functions in diabetes mellitus (DM) rats.
In this study, we mimicked hyperglycemia condition in neonatal rat (1-3 day) cardiomyocytes with HG model. Cardiomyocytes were incubated in 30 mM HG in the presence or absence of KMUP-3 (1 to 10 &;#61549;M). An experimental diabetic rat model was induced by 65 mg/kg of streptozoticin (STZ). KMUP-3 was intraperitoneally injected at a dose of 1 mg/kg. Cardiac functions were evaluated by serial echocardiography. We found that KMUP-3 treatment attenuated HG-induced cell death by MTT assay. Additionally, KMUP-3 also inhibited HG-induced apoptosis, with associated increase of Bcl-2 protein, and decrease of Bax protein and caspase-3 cleavage. Microtubule-associated protein I light chain 3-II (LC3-II) is the key protein associated with autophagy. KMUP-3 significantly enhanced production of LC3-II and phosphorylation of AMPK in a time-dependent manner. As expected, KMUP-3 pretreatment dose-dependently reduced the HG-induced decrease of LC3-II, Atg7, and phosphor-AMPK expression. Fractional shortening (FS) and ejection fraction (EF), the index of left ventricular systolic function, were significantly decreased in DM group. Then compared with DM group, these changes were attenuated when diabetic rats were treated with KMUP-3 (P<0.05).
In summary, KMUP-3 attenuates HG-induced cardiomyocytes apoptosis by inducing autophagy. These findings suggest that KMUP-3 may have great therapeutic potential in the treatment of diabetic cardiomyopathy.
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