This Article Full Text Full Text (PDF) All Versions of this Article: 99/5/468    most recent 01.RES.0000239410.65551.b3v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sun, J. Articles by Liao, J. K. Search for Related Content PubMed PubMed Citation Articles by Sun, J. Articles by Liao, J. K. Related Collections Biochemistry and metabolism Apoptosis Cell signalling/signal transduction Ischemic biology - basic studies Oxidant stress Related Article

(Circulation Research. 2006;99:468.)
© 2006 American Heart Association, Inc.

Molecular Medicine

FHL2/SLIM3 Decreases Cardiomyocyte Survival by Inhibitory Interaction With Sphingosine Kinase-1

Jianxin Sun, Guijun Yan, Aixia Ren, Bei You, James K. Liao

From the Department of Cell Biology and Molecular Medicine (J.S., G.Y., A.R., B.Y.), University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark; Department of Pharmacology (S.J.), Second Military Medical University, Shanghai, China; and Vascular Medicine Research Unit (J.K.L.), Brigham & Women’s Hospital and Harvard Medical School, Boston, Mass.

Correspondence to Jianxin Sun, Department of Cell Biology and Molecular Medicine, UMDNJ-New Jersey Medical School, 185 South Orange Ave, MGB G-653, Newark, NJ 07103. E-mail sunj1{at}umdnj.edu

Sphingosine kinase-1 (SK1) is a key enzyme catalyzing the phosphorylation of sphingosine to sphingosine-1–phosphate (S1P). Recent studies suggest that SK1, and its product S1P, regulate diverse biological functions, including cell growth, differentiation, proliferation, and apoptosis. S1P may also play an important role in cardiac development and ischemic preconditioning, but the mechanism underlying these effects is not known. Using a yeast 2-hybrid screen with SK1 as bait and a cardiac cDNA library to identify novel proteins involved in regulating SK1 activity in cardiomyocytes, we identified the LIM-only factor FHL2 (SLIM3) as a SK1-interacting protein in both yeast and mammalian cells. FHL2, but not FHL1 or FHL3, interacted with SK1, and FHL2 colocalized with SK1 in the cytoplasm. The interaction sites with SK1 consisted of at least 4 LIM domains in FHL2, whereas the C-terminal portion of SK1 mediates the binding of FHL2 in SK1. Overexpression of FHL2 attenuated the activity and antiapoptotic effects of SK1. Indeed, endothelin-1, which is a potent survival factor in cardiomyocytes, inhibited FHL2-SK1 association and increased SK1 activity. These findings indicate that FHL2 is a novel inhibitor of SK1 activity in cardiomyocytes and suggest that targeting FHL2 for inhibition may prevent myocardial apoptosis through activation of SK1.

Key Words: sphingosine kinase • FHL2 • cardiac myocytes • apoptosis

Related Article:

Toward Solving the Riddle: The Enigma Becomes Less Mysterious

Joel S. Karliner
Circ. Res. 2006 99: 465-467. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				H. Hayashi, H. Nakagami, Y. Takami, H. Koriyama, M. Mori, K. Tamai, J. Sun, K. Nagao, R. Morishita, and Y. Kaneda FHL-2 Suppresses VEGF-Induced Phosphatidylinositol 3-Kinase/Akt Activation via Interaction With Sphingosine Kinase-1 Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 909 - 914. [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.-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]

				G. Yan, S. Chen, B. You, and J. Sun Activation of sphingosine kinase-1 mediates induction of endothelial cell proliferation and angiogenesis by epoxyeicosatrienoic acids Cardiovasc Res, May 1, 2008; 78(2): 308 - 314. [Abstract] [Full Text] [PDF]

				T. M. Leclercq, P. A. B. Moretti, M. A. Vadas, and S. M. Pitson Eukaryotic Elongation Factor 1A Interacts with Sphingosine Kinase and Directly Enhances Its Catalytic Activity J. Biol. Chem., April 11, 2008; 283(15): 9606 - 9614. [Abstract] [Full Text] [PDF]

				A. Ren, G. Yan, B. You, and J. Sun Down-regulation of Mammalian Sterile 20-Like Kinase 1 by Heat Shock Protein 70 Mediates Cisplatin Resistance in Prostate Cancer Cells Cancer Res., April 1, 2008; 68(7): 2266 - 2274. [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]

				B. You, A. Ren, G. Yan, and J. Sun Activation of Sphingosine Kinase-1 Mediates Inhibition of Vascular Smooth Muscle Cell Apoptosis by Hyperglycemia Diabetes, May 1, 2007; 56(5): 1445 - 1453. [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]

				J. Fielitz, E. van Rooij, J. A. Spencer, J. M. Shelton, S. Latif, R. van der Nagel, S. Bezprozvannaya, L. de Windt, J. A. Richardson, R. Bassel-Duby, et al. Loss of muscle-specific RING-finger 3 predisposes the heart to cardiac rupture after myocardial infarction PNAS, March 13, 2007; 104(11): 4377 - 4382. [Abstract] [Full Text] [PDF]

				J. S. Karliner Toward Solving the Riddle: The Enigma Becomes Less Mysterious Circ. Res., September 1, 2006; 99(5): 465 - 467. [Full Text] [PDF]