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

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. Here, we investigated in a cardiomyocyte‐restricted Nrf2 transgenic mice (Nrf2‐TG) the direct effect of Nrf2 on cardiomyocytes in DCM and its mechanism. 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. Compared to wild‐type mice, Nrf2‐TG mice showed resistance to diabetic cardiomyopathy in a streptozotocin‐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. These results showed that Nrf2 can directly act on cardiomyocytes to exert a cardioprotective role. Mechanistically, the cardioprotective effects of Nrf2 depend on its antioxidation activity, partially through improving glucose and lipid metabolism by directly targeting lipid metabolic pathway of AMPK/Sirt1/PGC‐1α activation via upstream genes of sestrin2 and LKB1, and indirectly enabling AKT/GSK‐3β/HK‐Ⅱ activity via AMPK mediated p70S6K inhibition. Nrf2 can directly act on cardiomyocytes to play a cardioprotective role and inhibit DCM. Nrf2 inhibits cardiac remodeling and dysfunction caused by type 1 diabetes mellitus through activating Akt/GSK‐3β/HK‐II glucose metabolism signaling and AMPK/Sirt1/PGC‐1α lipid metabolism signaling in cardiomyocytes.