A novel role for mitochondrial sphingosine-1-phosphate produced by sphingosine kinase-2 in PTP-mediated cell survival during cardioprotection
2011
Although mitochondria are key determinants of myocardial injury during ischemia–reperfusion (I/R), their interaction with critical
cytoprotectivesignaling systems is not fully understood.
Sphingosine-1-phosphate (S1P) produced by
sphingosine kinase-1 protects the heart from I/R damage. Recently a new role for mitochondrial S1P produced by a second isoform of
sphingosine kinase,
SphK2, was described to regulate complex IV assembly and respiration via interaction with mitochondrial
prohibitin-2. Here we investigated the role of
SphK2in
cardioprotectionby preconditioning. Littermate (WT) and
sphk2−/− mice underwent 45 min of in vivo ischemia and 24 h reperfusion. Mice received no intervention (I/R) or preconditioning (PC) via 5 min I/R before the index ischemia. Despite the activation of PC-
cytoprotectivesignaling pathways in both groups, infarct size in
sphk2−/− mice was not reduced by PC (42 ± 3% PC vs. 43 ± 4% I/R, p = ns) versus WT (24 ± 3% PC vs. 43 ± 3% I/R, p < 0.05).
sphk2−/− mitochondria exhibited decreased oxidative phosphorylation and increased susceptibility to permeability transition (PTP). Unlike WT, PC did not prevent ischemic damage to electron transport or the increased susceptibility to PTP. To evaluate the direct contribution to the resistance of mitochondria to
cytoprotection,
SphK2, PHB2 or cytochrome oxidase subunit IV was depleted in cardiomyoblasts. PC protection was abolished by each knockdown concomitant with decreased PTP resistance. These results point to a new action of S1P in
cardioprotectionand suggest that the mitochondrial S1P produced by
SphK2is required for the downstream protective modulation of PTP as an effector of preconditioning protection.
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