Abstract 219: The Formin mDia1 Is A Novel Mediator Of Injury In Ischemia/Reperfusion
mDia1, a member of the formin family and an effector of Rho GTPases, has emerged as a downstream effector of RAGE signaling. RAGE has been shown to stimulate the deleterious effects of ischemia/reperfusion injury. The goal of this study was to elucidate the role of mDia1 in the heart after ischemia/reperfusion injury. In mouse hearts subjected to left anterior coronary artery occlusion (LAD) for 30 minutes followed by 48 hours of reperfusion, there is a ten-fold increase in mDia1 protein expression compared to sham. We thus tested the effects of deletion of mDia1; adult male mDia1-/- mice and wild type littermates (WT) were subjected to LAD or sham surgery. Infarct size in mDia1-/- mice was significantly reduced by 15% compared to WT after LAD (32.6 vs. 27.6% infarct area, respectively; p=0.008). LV function after LAD was improved in mDia-/- mice, as evidenced by a significant increase in fractional shortening compared to WT (34.6 vs. 27.1%; p=0.005). ChIP studies of cardiac tissue post-LAD revealed that there was an interaction between mDia1 protein and Egr1, Serca2a, and SRF genes in WT mice subjected to LAD but not in sham mice. Furthermore, EGR1 protein levels were reduced in the nuclear fraction of mDia1-/- mouse hearts after LAD compared to WT and SERCA2A protein levels were elevated in mDia1-/- mice after LAD compared to WT. These effects were confirmed in mDia1-expressing AC16 human ventricular myocytes subjected to hypoxia for 30 minutes followed by reoxygenation for 60 minutes (H/R). Compared to normoxia, mDia1 protein was increased in H/R cells by three-fold, and there was an interaction between mDia1 protein and genes for Egr1 and Serca2a in the H/R cells but not in normoxic cells. mDia1-/- and WT hearts were also isolated and subjected to 30 minutes of global ischemia followed by 60 minutes of reperfusion. In mDia1-/- hearts, there was improved LVDP recovery compared to WT (63.3 vs. 33.7%, respectively). Taken together, these data suggest that mDia1 deletion mediates cardioprotection in ischemia/reperfusion injury through downstream interactions with SRF, SERCA2A, and EGR1.
- © 2013 by American Heart Association, Inc.