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(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

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