Sphingosine can pre‐ and post‐condition heart and utilizes a different mechanism from sphingosine 1‐phosphate

Abstract

Consistent with previous reports, sphingosine at a high concentration (5 microM) was cardiotoxic as evidenced by increased infarct size in response to ischemia/reperfusion in an ex vivo rat heart. Sphingosine 1-phosphate (S1P) at 5 microM was cardioprotective. However, at a physiologic concentration (0.4 microM) sphingosine as well as S1P was effective in protecting the heart from ischemia/reperfusion injury both when perfused prior to 40 min of ischemia (preconditioning) or when added to reperfusion media following ischemia (postconditioning). Protection by sphingosine and S1P was evidenced with both pre- and post-conditioning by a >75% recovery of left ventricular developed pressure during reperfusion and a decrease in infarct size from 45% of the risk area to less than 8%. When VPC23019, an S1P(1and3)G-protein coupled receptor antagonist, was added to the preconditioning or postconditioning medium along with S1P, it completely blocked S1P-induced protection. However, VPC 23019 did not affect the ability of 0.4 microM sphingosine to either precondition or postcondition hearts. Studies of preconditioning revealed that inhibition of protein kinase C with GF109203X blocked preconditioning by S1P. However, GF109203X did not affect preconditioning by 0.4 microM sphingosine. Likewise, cotreatment with the PI3 kinase inhibitor wortmanin blocked preconditioning by S1P but not by sphingosine. By contrast, inhibition of protein kinase G with KT5823 had no effect on S1P preconditioning but completely eliminated preconditioning by sphingosine. Also, the protein kinase A inhibitory peptide 14-22 amide blocked preconditioning by sphingosine but not S1P. These data reveal for the first time that sphingosine is not toxic at physiologic concentrations but rather is a potent cardioprotectant that utilizes a completely different mechanism than S1P; one that is independent of G-protein coupled receptors and utilizes cyclic nucleotide-dependent pathways.

P2X7 receptor agonists pre- and postcondition the heart against ischemia-reperfusion injury by opening pannexin-1/P2X7 channels

“…1). As previously shown (32)(33)(34)(35), the recovery of hemodynamic function, assessed as LVDP, is poor, and at the end of 40 min of reperfusion, these hearts have large areas of infarction by TTC staining. Treating ex vivo hearts at the midpoint of the equilibration period (before ischemia) with a 1-min perfusion of 0.4 M ATP greatly improved the recovery of LVDP during reperfusion (79 Ϯ 5% of its preischemic value compared with 6 Ϯ 2% for 1 min buffer treatment).…”

“…PI3K and Akt are important components of the cardioprotection signaling pathway that leads to the key cell survival molecule phospho-Akt (11,17,23,24,34,37). As reported previously (37) and shown in Fig.…”

“…This protection results from the release from myocytes of endogenous cardioprotectants that bind to cell surface G protein-coupled receptors (GPCRs) and trigger cell signaling pathways that lead to protection (3,10,20,24,25,28,(33)(34)(35). We found that the release of these endogenous cardioprotectants from myocytes in response to ischemic preconditioning or ischemic postconditioning occurs via the opening of a channel formed by the interaction of a P2X 7 purinergic receptor with a pannexin-1 hemichannel (36, 37).…”

Apelin-13 limits infarct size and improves cardiac postischemic mechanical recovery only if given after ischemia

“…This study shows that 0.5 M apelin-13 protects the rat heart only when infused during the first 20 min of reperfusion but not when given before ischemia. Thus, whereas several compounds mimic both preC and postC (12,44,48), apelin-13 mimics postC only.…”

Sphingolipids in cardiovascular and cerebrovascular systems: Pathological implications and potential therapeutic targets

“…Although there is abundant evidence that sphingosine is toxic to cells [25,28] , diverse function by concentration dependence of sphingosine has been reported. Vessey et al [35] recently reported that at lower dose (submicromolar), a more physiologic concentrations, sphingosine has been shown to be cardioprotective in isolated Langendorff-perfused rat hearts subjected to ischemia/reperfusion injury. Unlike S1P, sphingosine-induced cardioprotection seems to be mediated by cyclic nucleotide-dependent protein kinase A and G (PKA and PKG) pathways [35] .…”