A novel role for mitochondrial sphingosine-1-phosphate produced by sphingosine kinase-2 in PTP-mediated cell survival during cardioprotection |
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Authors: | Gomez Ludovic Paillard Melanie Price Megan Chen Qun Teixeira Geoffrey Spiegel Sarah Lesnefsky Edward J |
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Institution: | (1) Department of Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA;(2) Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA;(3) McGuire Veterans Affairs Medical Center, Richmond, VA 23249, USA;(4) INSERM U886, Universit? Claude Bernard Lyon I, 69373 Lyon, France; |
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Abstract: | Although mitochondria are key determinants of myocardial injury during ischemia–reperfusion (I/R), their interaction with
critical cytoprotective signaling 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 SphK2 in cardioprotection by 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-cytoprotective signaling 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 cardioprotection and suggest that the mitochondrial S1P produced by SphK2 is required
for the downstream protective modulation of PTP as an effector of preconditioning protection. |
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