Chasing sphingosine-1-phosphate, a lipid mediator for cardiomyocyte survival

See article by Tao et al.[5](pages 56–63) in this issue. Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite that regulates many essential biological processes in various cells and tissues. S1P may act as an extracellular ligand to specific G protein-coupled S1P receptors (S1P1–5) or as an intracellular second messenger. Sphingosine is derived from cleavage of ceramide by ceramidases in the sphingolipid degradative pathway. It can be catalyzed by sphingosine kinases (SphK1 and 2) into S1P, which is then degraded by a S1P lyase and S1P phosphohydrolases. S1P is most abundant in platelets, but it can also be synthesized in various cells such as cardiomyocytes. A “sphingolipid rheostat” hypothesis suggests that the relative levels of these lipids are important determinants of cell fate [1]. In fact, both ceramide and S1P are known to be involved in cardiomyocyte survival and apoptosis. It has been shown that ceramide induces cardiomyocyte apoptosis in the heart [2], and it has been proposed that it is a mediator of cardiomyocyte death in myocardial ischemic–reperfusion injury [3]. On the contrary, S1P exerts an anti-apoptosis effect in rat cultured neonatal cardiomyocytes [4]. However, a detailed signaling pathway by which S1P exerts its anti-apoptotic effect in cardiomyocytes remains obscure. In this issue of Cardiovascular Research, Tao et al. [5] present new evidence to show that sphingosine kinases 1 (SphK1) deficiency in adult cardiomyocytes aggravates cell death induced by hypoxia and glucose deprivation, providing strong evidence for an essential role of SphK1-catalyzed S1P in cardiomyocyte survival. The advantage of the cardiomyocyte study is that it excludes potential confounding effects of S1P on other cell types. More importantly, studies on cardiomyocytes isolated from SphK1 null mice provide a definitive approach to identifying SphK1's function in the anti-apoptotic effect of S1P in cardiomyocytes. In addition, the action of increased S1P due to SphK1 activation can be blocked both at the S1PR and the G-protein (Gi) levels, inferring that the intracellular S1P must be exported from the cell and bind to its receptors to exert its pro-survival effects. Tao et al. build upon their previous findings that S1P from endogenous and exogenous sources can protect cardiomyocytes from hypoxia-induced apoptosis. They further extend their previous findings on an important role of SphK1 activities in regulating intracellular S1P and hence cell survival based on studies using compounds inhibiting or activating SphK1 activities [4,6]. A recent study demonstrated that knockdown of a newly identified endogenous SphK1 inhibitor, the four-and-a-half LIM domain 2 (FHL2), protects cardiomyocytes from apoptosis [7]. Moreover, another recent study demonstrated that increased intracellular reactive oxygen species (ROS) leads to degradation of SphK1, and this is proposed as a key mechanism of ROS-induced apoptosis of cardiomyocytes [8]. The current study by Tao et al. conclusively establishes SphK1 as an important signaling point in the S1P survival pathway by studying cardiomyocytes from SphK1 null mice. The activation of SphK1 and prevention of SphK1 inhibition would be logical approaches for potential therapeutic interventions for cardiomyocyte apoptosis. It is interesting that another sphingosine kinase, SphK2, remains unchanged in the SphK1 null cardiomyocytes. Even though a previous report indicated that SphK1 and SphK2 may have opposite roles in cell survival [9], it remains unclear how SphK2 is involved in cell fate determination in cardiomyocytes. Further studies on how apoptotic stimuli influence the activities of individual SphKs and S1P signaling in cardiomyocytes should provide in-depth mechanistic insights. Another unanswered question is how the changes of SphK1 activities would affect the intracellular levels of ceramide and how much of these changes contribute to altering cell fate. In combination with pharmacological intervention, i.e., to specifically inhibit S1PRs, the current study provides convincing evidence that S1P is an important second messenger that acts on its receptors to exert a pro-survival effect in mouse adult cardiomyocytes. The binding of S1P to its receptors on the cardiomyocyte plasma membrane is required for its anti-apoptotic effect. It has been reported that both transcripts and proteins of S1P1, 3, 5 are expressed in cardiomyocytes [10]. With the current technique, it is difficult to identify the particular S1PR or S1PRs involved in S1P-mediated cell survival signaling. Genetic mouse models lacking the specific, key enzyme converting sphingosine into key S1P converting enzymes and S1PRs should provide specific information on the mechanisms of S1P signaling. Indeed, a recent study demonstrated that exogenous S1P protects against I/R injury and that this protection is abolished in S1P3 receptor null mice [11]. More studies on other S1PRs are to be warranted to identify any potential differential roles of various S1PRs in cardiomyocytes. Such studies should provide clarity for mechanistic understanding of specific S1P–S1PR action. A main hurdle preventing the therapeutic use of S1P is the previous findings that S1P influences electrophysiological properties of cardiomyocytes. It has been shown that S1P stimulates an inward-rectifying potassium current in guinea pig atrial myocytes leading to a shortening of the action potential [12]. S1P can also induce sinus tachycardia and coronary vasoconstriction in the canine heart [13]. In rat ventricular myocytes, S1P was found to depress excitability by reversibly decreasing the current necessary to elicit action potentials [14]. In addition, S1P induces calcium overload via the S1P1 receptor in neonatal rat cardiac myocytes [15]. Therefore, these confounding effects of S1P on cardiomyocytes and on an intact heart pose a major obstacle for its therapeutic use. To develop an analog of S1P that activates S1P receptors but has no side-effect on action potentials would be one goal for the future. This work was supported by grants from the NIH (S06GM08248, 1R01HL085499 and 1R01HL084456), a scientist development award from the American Heart Association national center.