Copyright © 2007, European Society of Cardiology
Deletion of the Sphingosine Kinase-1 gene influences cell fate during hypoxia and glucose deprivation in adult mouse cardiomyocytes
aCardiology Section, Veterans Affairs Medical Center and Department of Medicine, University of California, San Francisco, CA 94121, United States
bLiver Study Unit, Veterans Affairs Medical Center and Department of Medicine, University of California, San Francisco, CA 94121, United States
cDepartment of Cardiology, Ruijin Hospital, Jiao Tong University, Shanghai 200025, China
dCardiovascular Research Institute, University of California, San Francisco, CA 94143, United States
* Corresponding author. Cardiology Section (111C5), 4150 Clement Street, San Francisco, CA 94121, U.S.A. Tel.: +1 415 221 4810x3171; fax: +1 415 750 6959. Email address: Joel.Karliner{at}med.va.gov
Objectives: Activation of sphingosine kinase (SphK), which has two known isoforms, is responsible for the synthesis of sphingosine 1-phosphate (S1P), a cell survival factor. We tested the following hypotheses: 1] cardiac myocytes null for the SphK1 gene are more vulnerable to the stress of hypoxia+glucose deprivation; 2] the monoganglioside GM-1, which activates SphK via protein kinase C 
, is ineffective in SphK1-null myocytes; 3] S1P generated by SphK activation requires cellular export to be cardioprotective.
Methods: We cultured adult mouse cardiac myocytes from wildtype and SphK1-null mice (deletion of exons 3–6) and measured cell viability by trypan blue exclusion.
Results: In wildtype adult mouse cardiomyocytes subjected to 4 h of hypoxic stress+glucose deprivation, cell viability was significantly higher than in SphK1-null cardiomyocytes. SphK1-null cells also displayed more mitochondrial cytochrome C release. Cell death induced by hypoxia+glucose deprivation was substantially prevented by pretreatment with exogenous S1P in both wildtype and SphK1-null myocytes, but S1P was effective at a lower concentration in wildtype cells. Hence, the absence of the Sphk1 gene did not affect receptor coupling or downstream signal transduction. Pretreatment for 1 h with 1 µM of the monoganglioside GM-1 increased survival in wildtype cells, but not in SphK1-null myocytes. Thus, activation of SphK1 by GM-1 leads to cell survival. In wildtype cells, enhanced survival produced by GM-1 was abrogated by pretreatment either with 300 nM of the S1P1 receptor-selective antagonist VPC23019 or with 100 ng/ml of pertussis toxin for 16 h before exposure to hypoxia+glucose deprivation.
Conclusion: As the effect of GM-1 is blocked both at the receptor and the G-protein (Gi) levels, we conclude that S1P generated by GM-1 treatment must be exported from the cell and acts in a paracrine or autocrine manner to couple with its cognate receptor.
KEYWORDS Sphingosine kinase; Sphingosine-1-phosphate; Cytochrome C; Hypoxia
Time for primary review 28 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. A. Vessey, L. Li, N. Honbo, and J. S. Karliner Sphingosine 1-phosphate is an important endogenous cardioprotectant released by ischemic pre- and postconditioning Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1429 - H1435. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Ader, B. Malavaud, and O. Cuvillier When the Sphingosine Kinase 1/Sphingosine 1-Phosphate Pathway Meets Hypoxia Signaling: New Targets for Cancer Therapy Cancer Res., May 1, 2009; 69(9): 3723 - 3726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Karliner Sphingosine kinase regulation and cardioprotection Cardiovasc Res, May 1, 2009; 82(2): 184 - 192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. K. Means and J. H. Brown Sphingosine-1-phosphate receptor signalling in the heart Cardiovasc Res, May 1, 2009; 82(2): 193 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-C. Yeh, H. Li, D. Malhotra, M.-C. Huang, B.-Q. Zhu, E. J. Goetzl, D. A. Vessey, J. S. Karliner, and M. J. Mann Sphingolipid signaling and treatment during remodeling of the uninfarcted ventricular wall after myocardial infarction Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H1193 - H1199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Schnitzer, A. Weigert, J. Zhou, and B. Brune Hypoxia Enhances Sphingosine Kinase 2 Activity and Provokes Sphingosine-1-Phosphate-Mediated Chemoresistance in A549 Lung Cancer Cells Mol. Cancer Res., March 1, 2009; 7(3): 393 - 401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Ader, L. Brizuela, P. Bouquerel, B. Malavaud, and O. Cuvillier Sphingosine Kinase 1: A New Modulator of Hypoxia Inducible Factor 1{alpha} during Hypoxia in Human Cancer Cells Cancer Res., October 15, 2008; 68(20): 8635 - 8642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-Q. Jin, J. S. Karliner, and D. A. Vessey Ischaemic postconditioning protects isolated mouse hearts against ischaemia/reperfusion injury via sphingosine kinase isoform-1 activation Cardiovasc Res, July 1, 2008; 79(1): 134 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Anelli, C. R. Gault, A. B. Cheng, and L. M. Obeid Sphingosine Kinase 1 Is Up-regulated during Hypoxia in U87MG Glioma Cells: ROLE OF HYPOXIA-INDUCIBLE FACTORS 1 AND 2 J. Biol. Chem., February 8, 2008; 283(6): 3365 - 3375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. T. McCloskey, S. Turcato, G.-Y. Wang, L. Turnbull, B.-Q. Zhu, T. Bambino, A. P. Nguyen, D. H. Lovett, R. A. Nissenson, J. S. Karliner, et al. Expression of a Gi-coupled receptor in the heart causes impaired Ca2+ handling, myofilament injury, and dilated cardiomyopathy Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H205 - H212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhang, N. Honbo, E. J. Goetzl, K. Chatterjee, J. S. Karliner, and M. O. Gray Signals from type 1 sphingosine 1-phosphate receptors enhance adult mouse cardiac myocyte survival during hypoxia Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3150 - H3158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Nishino, I. Webb, and M. S. Marber Sphingosine kinase isoforms and cardiac protection Cardiovasc Res, October 1, 2007; 76(1): 3 - 4. [Full Text] [PDF]
|
|
|
|
|
|
Z.-Q. Jin, J. Zhang, Y. Huang, H. E. Hoover, D. A. Vessey, and J. S. Karliner A sphingosine kinase 1 mutation sensitizes the myocardium to ischemia/reperfusion injury Cardiovasc Res, October 1, 2007; 76(1): 41 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Yang Chasing sphingosine-1-phosphate, a lipid mediator for cardiomyocyte survival Cardiovasc Res, April 1, 2007; 74(1): 4 - 5. [Full Text] [PDF]
|
|