Nrf2 Exaggerates Cardiomyopathy Associated with Type 1 Diabetes in Mice

Nuclear factor-erythroid factor 2-related factor 2 (Nrf2), a transcription factor for cellular defense against oxidative stress and other insults, has been postulated to be an inhibitor of diabetes and diabetic cardiomyopathy. However, this notion has been challenged by the detrimental role of Nrf2 in the pathogenesis of diabetes and diabetic cardiomyopathy. Thus, we investigated the nature of the Nrf2-mediated dichotomy in a mouse model of streptozotocin (STZ)-induced type 1 diabetes over a time period of 9 months. We found that global Nrf2 knockout (Nrf2 KO) increased the death rate in the setting of STZ-induced diabetes, but it partly protected against STZ-induced diabetes and insulin-resistance in both male and female mice. Nrf2 KO hardly affected the onset and the progression of cardiac dysfunction associated with the diabetes by 6 months in both male and female mice; however, it partly prevented the progression of cardiac dysfunction at 9 months. Cardiomyocyte hypertrophy, cardiac fibrosis, and cardiac oxidative stress associated with the diabetes not at 3 months but at 6 and 9 months were inhibited by Nrf2 KO in both male and female mice. In addition, cardiomyocyte-restricted (CR) Atg5 KO had minimal impact on the blood glucose level, but exaggerated the diabetic cardiomyopathy, which could be attenuated in part by additional Nrf2 KO. At the molecular level, diabetes-induced autophagy impairment turned off Nrf2-operated antioxidant defense while switching on Nrf2-mediated detrimental signaling to cardiomyocytes. Taken together, our findings reveal that Nrf2 is cardiac protective when myocardial autophagy is intact; however, it becomes detrimental to the heart when myocardial autophagy is impaired due to a chronic diabetic setting.