Hydrogen Sulfide Preconditions the db/db Diabetic Mouse Heart

29 Hydrogen sulfide (H2S) therapy protects non-diabetic animals in various models 30 of myocardial injury, including acute myocardial infarction and heart failure. 31 Here, we sought to examine if H2S therapy provides cardioprotection in the 32 setting of Type-2 diabetes. H2S therapy in the form of sodium sulfide (Na2S) 33 beginning 24 hours or 7 days prior to myocardial ischemia significantly 34 decreased myocardial injury in db/db diabetic mice (12 weeks of age). In an effort 35 to evaluate the signaling mechanism responsible for the observed 36 cardioprotection, we focused on the role of Nrf2 signaling. Our results indicate 37 that diabetes does not alter the ability of H2S to increase the nuclear localization 38 of Nrf2, but does impair aspects of Nrf2 signaling. Specifically, the expression of 39 NADPH;quinine oxidoreductase 1 (NQO1) was increased after the acute 40 treatment, whereas the expression of heme-oxygenase-1 (HO-1) was only 41 increased after 7 days of treatment. This discrepancy was found to be the result 42 of an increased nuclear expression of Bach1, a known repressor of HO-1 43 transcription, which blocked the binding of Nrf2 to the HO-1 promoter. Further 44 analysis, revealed that 7 days of Na2S treatment overcame this impairment by 45 removing Bach1 from the nucleus in an Erk1/2-dependent manner. Our findings 46 demonstrate for the first time that exogenous administration of Na2S attenuates 47 myocardial ischemia-reperfusion injury in db/db mice suggesting the potential 48 therapeutic effects of H2S in treating a heart attack in the setting of Type-2 49 diabetes. 50