Published online before print March 13, 2003, doi: 10.1161/01.RES.0000066290.29715.67
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Submitted on January 7, 2003
Revised on February 11, 2003
Accepted on March 3, 2003
Factor Associated With Neutral Sphingomyelinase Activation and Its Role in Cardiac Cell Death
Nicole W. O'Brien ;
From the SDSU Heart Institute and Department of Biology, San Diego State University, San Diego, Calif.
* To whom correspondence should be addressed. E-mail: rsabba{at}sunstroke.sdsu.edu.
Generation of proapoptotic sphingolipids by neutral sphingomyelinase activation is an early response to hypoxia/reoxygenation (HR) in cardiomyocytes. Factor associated with neutral sphingomyelinase activation (FAN) mediates activation of sphingomyelinase and subsequent apoptosis. However, the participation of FAN in HR-induced cardiomyocyte cell death has not been elucidated. We therefore investigated the expression and role of FAN in rat cardiomyocytes. A cDNA was isolated from rat heart encoding putative rat FAN. Reverse transcriptase-polymerase chain reaction, immunoelectron microscopy, and immunofluorescence demonstrated for the first time the expression of FAN specifically in rat cardiomyocytes. FAN expression was confirmed by the finding that expression of a dominant-negative FAN almost completely abrogated HR-induced cell death, whereas overexpression of wild-type FAN led to an increase. Treatment of FAN and DN-FAN-expressing cells with C2-ceramide produced substantial cell death, indicating DN-FAN exerts its protective action by interfering with the activation of the sphingolipid cascade. Taking these results together, we conclude that FAN is a previously undescribed and important HR signaling component in the heart and that inhibition of FAN may provide a novel intervention point for reducing ischemia/reperfusion injury.
Key words: FAN • sphingomyelinase • apoptosis • hypoxia
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