Cardioprotection mediated by sphingosine-1-phosphate and ganglioside GM-1 in wild-type and PKC epsilon knockout mouse hearts.
Sphingosine-1-phosphate (S1P) protects neonatal rat cardiac myocytes from hypoxic damage through unknown signaling pathways. We tested the hypothesis that S1P-induced cardioprotection requires activation by the epsilon-isoform of protein kinase C (PKC epsilon) by subjecting hearts isolated from PKC epsilon knockout mice and wild-type mice to 20 min of global ischemia and 30 min of reperfusion. Pretreatment with a 2-min infusion of 10 nM S1P improved recovery of left ventricular developed pressure (LVDP) in both wild-type and PKC epsilon knockout hearts and reduced the rise in LV end-diastolic pressure (LVEDP) and creatine kinase (CK) release. Pretreatment for 2 min with 10 nM of the ganglioside GM-1 also improved recovery of LVDP and suppressed CK release in wild-type hearts but not in PKC epsilon knockout hearts. Importantly, GM-1 but not S1P, increased the proportion of PKC epsilon localized to particulate fractions. Our results suggest that GM-1, which enhances endogenous S1P production, reduces cardiac injury through PKC epsilon-dependent intracellular pathways. In contrast, extracellular S1P induces equivalent cardioprotection through PKC epsilon-independent signaling pathways.
Jin
Zhu-Qiu
ZQ
Cardiology Section, Veterans Affairs Medical Center, San Francisco, California 94121, USA.
Zhou
Hui-Zhong
HZ
Zhu
Peili
P
Honbo
Norman
N
Mochly-Rosen
Daria
D
Messing
Robert O
RO
Goetzl
Edward J
EJ
Karliner
Joel S
JS
Gray
Mary O
MO
D000470:Alkaloids; D000818:Animals; D000831:Animals, Newborn; D053119:Benzophenanthridines; D015153:Blotting, Western; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005677:G(M1) Ganglioside / Q000494:pharmacology* / Q000502:physiology; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008246:Lysophospholipids; D051379:Mice; D018345:Mice, Knockout; D017202:Myocardial Ischemia; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000502:physiology; D016277:Ventricular Function, Left
D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008246:Lysophospholipids; D010617:Phenanthridines; C060506:sphingosine 1-phosphate; D005677:G(M1) Ganglioside; C016299:chelerythrine; D011493:Protein Kinase C; D003402:Creatine Kinase; D013110:Sphingosine