Nrf2 prevents diabetic cardiomyopathy via antioxidation and normalization of glucose and lipid metabolism in the heart

Objective Metabolic disorders and oxidative stress are the main causes of diabetic cardiomyopathy. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) exerts a powerful antioxidant effect and prevents the progression of diabetic cardiomyopathy. However, the mechanism of its cardiac protection and direct action on cardiomyocytes are not well understood. Methods In this study, cardiomyocyte-restricted Nrf2 transgenic mice (Nrf2-TG) were used to directly observe whether cardiomyocyte-specific overexpression of Nrf2 can prevent diabetic cardiomyopathy and correct glucose and lipid metabolism disorders in the heart. Results Compared to wild-type (WT) mice, Nrf2-TG mice showed resistance to diabetic cardiomyopathy in a streptozotocin (STZ)-induced type 1 diabetes mouse model. This was primarily manifested as improved echocardiography results as well as reduced myocardial fibrosis, cardiac inflammation, and oxidative stress. Conclusion These results showed that Nrf2 can directly act on cardiomyocytes to play a cardioprotective role. Mechanistically, the cardioprotective effects of Nrf2 depend on its antioxidation activity, partially through improving glucose and lipid metabolism by targeting the metabolic pathways of Akt/GSK-3 β/HK-II and AMPK/Sirt1/PGC-1α. * AGE : advanced glycation end ARE : antioxidant response element DCM : diabetic cardiomyopathy DM : diabetes mellitus EF : ejection fraction IHC : immunohistochemistry LV : left ventricle MDA : malondialdehyde STZ : streptozotocin WT : wild-type AMPK : AMP-activated protein kinase AKT : protein kinase B CTGF : connective tissue growth factor TGF-β1 : transforming growth factor 1 TNF-α : tumor necrosis factor alpha NQO1 : NAD(P)H: quinone oxidoreductase 1 CAT : catalase HO-1 : heme oxygenase 1 GLUT4 : glucose transporter 4 HK-II : Hexokinase-II PGC1-α : peroxisome proliferator-activated receptor-γ coactivator 1α LKB1 : liver kinase B1 GSK-3β : glycogen synthase kinase-3β 3-NT : 3-nitrotyrosine 4-HNE : 4-hydroxynonenal PPARδ : peroxisome proliferator-activated receptor delta CPT1 : carnitine palmitoyltransferase 1