Diabetic cardiomyopathy (DCM) is the main cause of heart failure in diabetic patients. Oxidative stress is considered to be one of the most important mechanisms. Thus, treatments targeting oxidative stress may represent suitable strategies for the effective prevention of DCM. Nuclear factor-E2-related factor 2 (Nrf2), a transcription factor responsible to oxidative stress, goes to nuclei and binds to antioxidant response elements of promoters of several antioxidant genes. Metallothionein (MT) is a protein that can bind heavy metal ions such as zinc (Zn) and also a potent scavenger of free radicals because of its high thiol contents. Genetically overexpressing either Nrf2 or MT specifically in the heart protects from DCM. In addition, we also showed that induction of MT with Zn or activation of Nrf2 with sulforaphane (SFN) also partially protects from DCM. Here we further explore whether up-regulation of both simultaneously with Zn and SFN combination would provide a better protection against DCM than either alone. OVE26 mouse is one genetic type 1 diabetic model with the diabetes onset at 3 weeks old and survival more than one year without insulin treatment, so it is very good model for diabetic complication study. 5-week old OVE26 mice were confirmed with hyperglycemia and then treated with SFN (0.5 mg/kg) and/or Zn (5 mg/kg) for 18 weeks. 23-week old OVE26 mice showed typical DCM, reflected by cardiac dysfunction and remodeling fibrosis by echocardiography and collagen staining, along significantly oxidative damage, and inflammatory responses using western blotting and real-time PCR. Treatment of OVE26 mice either with SFN or Zn significantly prevented the development of DCM, along with up-regulating Nrf2 function and overexpressing MT protein, respectively, but the best protection from DCM is in the SFN/Zn group. Therefore, combined use of SFN with Zn may provide a better protection against DCM than SFN or Zn alone for diabetic patients.
J. Wang: None. W. Wang: None. L. Cai: None.
American Diabetes Association (1-15-BS-018, 1-18-IBS-082 to L.C.)