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N, N‐Dimethylsphingosine protects murine heart and activates cytosolic sphingosine kinase by a PKCε dependent mechanism
Author(s) -
Jin Zhuqiu,
Karliner Joel S
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1121-b
Subject(s) - sphingosine , cardioprotection , protein kinase c , cytosol , sphingosine kinase , sphingosine kinase 1 , sphingosine 1 phosphate , chemistry , phosphorylation , microbiology and biotechnology , pharmacology , biology , biochemistry , medicine , ischemia , enzyme , receptor
Sphingosine kinase (SphK) is a key enzyme responsible for formation of sphingosine‐1‐phosphate (S1P). N, N‐Dimethylsphingosine (DMS) is recognized as a SphK inhibitor. However, the effect of DMS itself on cardiac function remains unknown. In Langendorff‐perfused mouse hearts, cardiac systolic and diastolic functions were recorded. Infarction size was measured by TTC staining. SphK activity was measured by radioassay of [ 3 H]sphingosine conversion to [ 3 H]S1P. Pretreatment with 1 μM DMS for 10 min protected mouse hearts against global ischemia and reperfusion injury: cardiac functions were improved and infarction size was reduced. The cardiac protection induced by DMS was abolished in PKCε‐null mouse hearts. Pretreatment with DMS increased cytosolic Akt phosphorylation (Ser 473) and Akt translocation from a triton‐insoluble fraction to the cytosol. Administration of 1 μM DMS increased cytosolic SK activity (ratio of [ 3 H]S1P/[ 3 H]Sphingosine) from 6.1+/−1.1 in the control group to 10.3+/−1.4 in the DMS group (n=4, P<0.05). This enhanced SK activity was abolished in PKCε‐null mouse hearts (n=4, P<0.05). DMS also increased PKCε translocation from the particulate to the cytosolic fraction with no effect on PKC alpha distribution. Co‐immunoprecipitation showed that SK1 interacted with PKCε and phosphorylation of PKCε on Ser729. Physiological concentration of DMS protects murine hearts against ischemia/ reperfusion injury. DMS activates SphK in the cytosol via a PKCε dependent mechanism. The PKCε‐SphK‐S1P pathway is involved in the cardioprotection induced by DMS. Supported by NIH 1P01HL068738‐01A1 to JSK.