sphingosine-phosphorylcholine and 3-methyladenine

Autophagy, evoked by diverse stresses including myocardial ischemia/reperfusion (I/R), profoundly affects the development of heart failure. However, the specific molecular basis of autophagy remains to be elucidated. Here we report that sphingosylphosphorylcholine (SPC), a bioactive sphingolipid, significantly suppressed apoptosis and induced autophagy in cardiomyocytes. Blocking this SPC evoked autophagy by 3-methyladenine (3MA)-sensitized cardiomyocytes to serum deprivation-induced apoptosis. Subsequent studies revealed that SPC downregulated the phosphorylation of p70S6K and 4EBP1 (two substrates of mTOR) but enhanced that of JNK when inducing autophagy. We identified SPC as a switch for the activity of Akt1, a supposed upstream modulator of both mTOR and JNK. Furthermore, β-cyclodextrin, which destroys membrane cholesterol, abolished the SPC-reduced phosphorylation of both Akt and PTEN, thus inhibiting SPC-induced autophagy. In conclusion, SPC is a novel molecule protecting cardiomyocytes against apoptosis by promoting autophagy. The lipid raft/PTEN/Akt1/mTOR signal pathway is the underlying mechanism and might provide novel targets for cardiac failure therapy.

Topics: Adenine; Animals; Animals, Newborn; Apoptosis; Autophagy; beta-Cyclodextrins; Carrier Proteins; Gene Expression Regulation; Intracellular Signaling Peptides and Proteins; MAP Kinase Kinase 4; Membrane Microdomains; Microtubule-Associated Proteins; Mitogen-Activated Protein Kinase 8; Myocytes, Cardiac; Phosphoproteins; Phosphorylcholine; Primary Cell Culture; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sphingosine; TOR Serine-Threonine Kinases