Abstract
ABSTRACTHyperglycemia is an independent risk factor for diabetic cardiomyopathy in humans; however, the underlying mechanisms have not been thoroughly elucidated. Zebrafish (Danio rerio) was used in this study as a novel vertebrate model to explore the signaling pathways of human adult cardiomyopathy. Hyperglycemia was induced by alternately immersing adult zebrafish in a glucose solution or water. The hyperglycemic fish gradually exhibited some hallmarks of cardiomyopathy such as myocardial hypertrophy and apoptosis, myofibril loss, fetal gene reactivation, and severe arrhythmia. Echocardiography of the glucose-treated fish demonstrated diastolic dysfunction at an early stage and systolic dysfunction at a later stage, consistent with what is observed in diabetic patients. Enlarged hearts with decreased myocardial density, accompanied by decompensated cardiac function, indicated that apoptosis was critical in the pathological process. Significant upregulation of the expression of Nkx2.5 and its downstream targets calreticulin (Calr) and p53 was noted in the glucose-treated fish. High-glucose stimulation in vitro evoked marked apoptosis of primary cardiomyocytes, which was rescued by the p53 inhibitor pifithrin-μ. In vitro experiments were performed using compound treatment and genetically via cell infection. Genetically, knockout of Nkx2.5 induced decreased expression of Nkx2.5, Calr and p53. Upregulation of Calr resulted in increased p53 expression, whereas the level of Nkx2.5 remained unchanged. An adult zebrafish model of hyperglycemia-induced cardiomyopathy was successfully established. Hyperglycemia-induced myocardial apoptosis was mediated, at least in part, by activation of the Nkx2.5–Calr–p53 pathway in vivo, resulting in cardiac dysfunction and hyperglycemia-induced cardiomyopathy.
Highlights
Diabetes mellitus has become a serious threat to public health in the 21st century
Hyperglycemia was induced by alternately immersing adult zebrafish in a glucose solution or water
Echocardiography of the glucose-treated fish demonstrated diastolic dysfunction at an early stage and systolic dysfunction at a later stage, consistent with what is observed in diabetic patients
Summary
It is estimated that the number of adults diagnosed with diabetes worldwide will increase to 300 million by 2025 (Boudina and Abel, 2007; King et al, 1998). Patients with diabetes are at a higher risk for cardiovascular diseases, which have become the major cause of mortality in the diabetic population (Boudina and Abel, 2007; Garcia et al, 1974). Accumulating evidence has shown increased apoptosis in the hearts of diabetic patients (Caiet al., 2002; Palmieriet al., 2008; Frustaci et al, 2000) and streptozotocin-treated animals (Caiet al., 2002; Kajstura et al, 2001), and indicated its important role in the development of diabetic cardiomyopathy (Huynh et al, 2014; Huynh et al, 2013)
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