Abstract P282: Increased Nuclear Localization of Fyn May Limit the Cardioprotective Effects of Hydrogen Sulfide by Interfering with Nrf2 Signaling
Background: Hydrogen sulfide (H2S) therapy reduces myocardial infarct size by up to 56% in non-diabetic mice. Here, we sought to examine if H2S could provide cardioprotection in the setting of diabetes.
Methods and Results: Diabetic mice (db/db) were subjected to 30 min of left coronary artery occlusion (LCA) followed by reperfusion for 24 hours at which time the extent of myocardial infarction was evaluated. Sodium sulfide (Na2S, 100 μ g/kg) administered at the time of reperfusion decreased infarct size relative the area-at-risk by 18% compared to vehicle treated animals (p<0.001). Previously, Na2S has been shown to increase the nuclear localization of Nrf-2 and upregulates its downstream target, heme oxygenase (HO)-1, in non-diabetic mice. To investigate if this cascade contributed to the observed cardioprotection, Na2S was administered (tail vein) to non-diabetic and diabetic mice and heart tissue was excised 1 hr and 24 hrs later. One hr following the administration of Na2S, the nuclear expression of Nrf2 was increased in both groups. In contrast, Na2S only increased the expression of HO-1 (24 hrs) in the non-diabetic heart. Further studies investigating Fyn, a tyrosine kinase known to inhibit Nrf2 signaling, revealed an upregulation of nuclear Fyn expression in the diabetic heart compared to the non-diabetic heart.
Conclusion: This data demonstrates the complexity of therapeutic intervention for diabetics following myocardial ischemia, as the robust cardioprotective effects of H2S in the non-diabetic state were found to be diminished in the diabetic state. This data also suggests that interference of Nrf2 signaling by Fyn may be responsible for the loss of protection.
- © 2011 by American Heart Association, Inc.