Copyright © 2006, European Society of Cardiology
Low dose N, N-dimethylsphingosine is cardioprotective and activates cytosolic sphingosine kinase by a PKC
dependent mechanism
Cardiology Section, VA Medical Center and Department of Medicine, University of California, San Francisco, CA 94121, USA
* Corresponding author. Cardiology Section (111C), 4150 Clement Street, San Francisco, CA 94121, USA. Tel.: +1 415 221 4810x3171; fax: +1 415 750 6950. Email address: joel.karliner{at}med.va.gov
Objective: N, N-Dimethylsphingosine (DMS) is recognized as an inhibitor of sphingosine kinase (SphK), a key enzyme responsible for the formation of sphingosine-1-phosphate (S1P). We previously showed that S1P was cardioprotective and that SphK was critical for myocardial ischemic preconditioning. Although DMS is an endogenous sphingolipid, its effect on cardiac function and cardioprotection at low concentration has not been studied.
Methods In Langendorff-perfused wild-type and protein kinase C (PKC)
-null mouse hearts, cardiac function, infarction size, and SphK activity were measured.
Results: Pretreatment with 0.3 µM and 1 µM DMS for 10 min protected against ischemia/reperfusion injury. Cardiac function (LVDP, ±dP/dtmax) was improved and infarction size was reduced. The cardiac protection induced by DMS was abolished in PKC-null mouse hearts. Administration of 1 µM DMS ex vivo increased cytosolic SphK activity. This enhanced SphK activity was abolished in PKC-null mouse hearts. DMS also increased PKC translocation from the particulate to the cytosolic fraction with no effect on PKC
distribution. Co-immunoprecipitation showed that SphK1 interacted with PKC phosphorylated on Ser729. DMS also increased cytosolic Akt phosphorylation (Ser 473) and Akt translocation from a Triton-insoluble fraction to the cytosol.
Conclusions: DMS has a biphasic effect on cardioprotection. Higher concentrations (10 µM) are inhibitory, whereas a low concentration (0.3 µM and 1 µM) of DMS protects murine hearts against ischemia/reperfusion injury. DMS activates SphK in the cytosol via a PKC dependent mechanism. The PKC–SphK–S1P–Akt pathway is involved in the cardiac protection induced by DMS.
KEYWORDS Preconditioning; Protein kinase C; Lipid signaling; Ischemia; Reperfusion
Time for primary review 14 days
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