Abstract
BackgroundDiabetes mellitus is an important risk factor for cardiomyopathy. Increasing oxidative stress may be one of the main factors of diabetic cardiomyopathy. A13, a newly synthesized curcumin analog, was proved to be superior to curcumin in biological activity. However, little know about how A13 performed in diabetic models. In this study, we evaluated the ability of curcumin analog A13 to alleviate oxidative stress and ameliorate fibrosis in the myocardium, and explore the underlying mechanisms.MethodsIntraperitoneal injection of streptozotocin (30 mg/kg in 0.1 M sodium citrate buffer, pH 4.5) induced diabetes in high-fat fed rats. The rats were respectively treated with a daily dose of curcumin or A13 via intragastric intubation for 8 weeks. Myocardial tissue sections were stained with hematoxylin–eosin; oxidative stress was detected by biochemical assays; activation of the Nrf2/ARE pathway was detected by Western blot, immunohistochemical staining and RT-qPCR; myocardial fibrosis was identified by Western blot and Masson trichrome staining.ResultsTreatment with curcumin analog A13 reduced the histological lesions of the myocardium in diabetic rats. Curcumin and A13 treatment decreased the malondialdehyde level and increased the activity of superoxide dismutase in the myocardium of diabetic rats. Molecular analysis and immunohistochemical staining demonstrated that dose of 20 mg/kg of A13 could activate the Nrf2/ARE pathway. Molecular analysis and Masson staining showed that curcumin analog A13 treatment significantly ameliorated fibrosis in myocardium of these diabetic rats.ConclusionTreatment with curcumin analog A13 protects the morphology of myocardium, restores the MDA levels and SOD activity, activates the Nrf2/ARE pathway and ameliorates myocardial fibrosis in diabetic rats. It may be a useful therapeutic agent for some aspects of diabetic cardiomyopathy.
Highlights
Diabetes mellitus is an important risk factor for cardiomyopathy
When the body is damaged by oxidative stress or some other agents, the heterodimer dissociates, and the free NF-E2-related factor 2 (NRF2) translocates into the nucleus and binds to the antioxidant reaction element (ARE), which increases the expression of the downstream effector proteins [3], like catalase (CAT) and NAD(P)H quinone dehydrogenase 1 (NQO1), to alleviate the oxidative damage and maintain the redox homeostasis
Treatment with curcumin analog A13 restored the morphology of the myocardial cells (Fig. 3c– e) to an extent comparable to that of control group and the recovery in the high-dose A13 treatment (H-A13) group was more significant, suggesting that curcumin analog A13 may protect the myocardium of rats against structural damage caused by hyperglycemia
Summary
Diabetes mellitus is an important risk factor for cardiomyopathy. Increasing oxidative stress may be one of the main factors of diabetic cardiomyopathy. The pathogenesis of DCM is complex, and increasing oxidative stress caused by disorder of glucose metabolism may be one of the key links of DCM [2]. NF-E2-related factor 2 (NRF2) binds to the Kelch-like ECH-related protein 1 (KEAP1) in the cytoplasm as a heterodimer. When the body is damaged by oxidative stress or some other agents, the heterodimer dissociates, and the free NRF2 translocates into the nucleus and binds to the antioxidant reaction element (ARE), which increases the expression of the downstream effector proteins [3], like catalase (CAT) and NAD(P)H quinone dehydrogenase 1 (NQO1), to alleviate the oxidative damage and maintain the redox homeostasis
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