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- Title
Metallothionein Is Downstream of Nrf2 and Partially Mediates Sulforaphane Prevention of Diabetic Cardiomyopathy.
- Authors
Junlian Gu; Yanli Cheng; Hao Wu; Lili Kong; Shudong Wang; Zheng Xu; Zhiguo Zhang; Yi Tan; Keller, Bradley B.; Honglan Zhou; Yuehui Wang; Zhonggao Xu; Lu Cai; Gu, Junlian; Cheng, Yanli; Wu, Hao; Kong, Lili; Wang, Shudong; Xu, Zheng; Zhang, Zhiguo
- Abstract
We have reported that sulforaphane (SFN) prevented diabetic cardiomyopathy in both type 1 and type 2 diabetes (T2DM) animal models via the upregulation of nuclear transcription factor erythroid 2-related factor 2 (Nrf2) and metallothionein (MT). In this study, we tested whether SFN protects the heart from T2DM directly through Nrf2, MT, or both. Using Nrf2-knockout (KO), MT-KO, and wild-type (WT) mice, T2DM was induced by feeding a high-fat diet for 3 months followed by a small dose of streptozotocin. Age-matched controls were given a normal diet. Both T2DM and control mice were then treated with or without SFN for 4 months by continually feeding a high-fat or normal diet. SFN prevented diabetes-induced cardiac dysfunction as well as diabetes-associated cardiac oxidative damage, inflammation, fibrosis, and hypertrophy, with increases in Nrf2 and MT expressions in the WT mice. Both Nrf2-KO and MT-KO diabetic mice exhibited greater cardiac damage than WT diabetic mice. SFN did not provide cardiac protection in Nrf2-KO mice, but partially or completely protected the heart from diabetes in MT-KO mice. SFN did not induce MT expression in Nrf2-KO mice, but stimulated Nrf2 function in MT-KO mice. These results suggest that Nrf2 plays the indispensable role for SFN cardiac protection from T2DM with significant induction of MT and other antioxidants. MT expression induced by SFN is Nrf2 dependent, but is not indispensable for SFN-induced cardiac protection from T2DM.
- Subjects
METALLOTHIONEIN; SULFORAPHANE; DIABETIC cardiomyopathy; TYPE 2 diabetes treatment; TRANSCRIPTION factors; HIGH-fat diet; STREPTOZOTOCIN; THERAPEUTICS; DIABETES complications; HEART metabolism; PROTEIN metabolism; TYPE 2 diabetes complications; ANIMAL experimentation; ANTINEOPLASTIC agents; BIOCHEMISTRY; DIABETES; DIET; ECHOCARDIOGRAPHY; HEART; PHENOMENOLOGY; LIPID peroxidation (Biology); METALLOPROTEINS; MICE; MYOCARDIUM; TYPE 2 diabetes; POLYMERASE chain reaction; PROTEINS; WESTERN immunoblotting; PHYTOCHEMICALS; PHARMACODYNAMICS
- Publication
Diabetes, 2017, Vol 66, Issue 2, p529
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db15-1274