Abstract 14772: A Novel Role For Sphingosine Kinase-2 In PTP-mediated Cell Survival During Cardioprotection
Rationale: Although mitochondria are key determinants of myocardial injury during ischemia-reperfusion (I/R), their interaction with critical cytoprotective signaling systems is not fully understood. Activation of sphingosine kinase-1 protects the heart from I/R damage. A second isoform of sphingosine kinase, sphingosine kinase-2 (SphK2), was described in the regulation of complex IV assembly and mitochondrial respiration via interaction with mitochondrial prohibitin-2 (PHB2).
Objective: In this study, we investigated the role of mitochondrial SphK2 in I/R injury.
Methods and Results: Littermate (WT) and sphk2-/- mice underwent 45 minutes of in vivo ischemia and 24 hours reperfusion. Mice received no intervention (I/R) or preconditioning (PC) via 5 minutes I/R before the index ischemia. Despite the activation of PC-cytoprotective pathways (phosphorylation of ERK1/2, Akt, STAT3 and GSK3β) in both groups, infarct size in sphk2-/- mice was not reduced by PC (42±3 % PC vs. 43±4 % I/R, p=ns) vs. WT (24±3 % PC vs. 43±3 % I/R, p<0.05). sphk2-/- mitochondria had decreased oxidative phosphorylation and increased susceptibility to permeability transition (PTP). Unlike WT, PC did not prevent ischemic damage to electron transport nor the increased susceptibility to PTP. To evaluate the direct contribution to the resistance of mitochondria to cytoprotection, SphK2, PHB2 or COX IV were depleted in cardiomyoblasts. PC protection was abolished by each knock-down with decreased PTP resistance.
Conclusions: SphK2 is required for the downstream protective modulation of PTP as an effector of PC protection. Direct or indirect defect in COX IV renders mitochondria resistant to cardioprotective modulation by upstream cytoprotective kinase cascades.
- © 2011 by American Heart Association, Inc.