Sphingosine 1-phosphate is an important endogenous cardioprotectant released by ischemic pre- and postconditioning

Abstract

Exogenous sphingosine 1-phosphate (S1P) is an effective cardioprotectant against ischemic injury. We have investigated the hypothesis that S1P is also an important endogenous cardioprotectant released during both ischemic preconditioning (IPC) and ischemic postconditioning (IPOST). IPC of ex vivo rat hearts was instituted by two cycles of 3 min ischemia-5 min reperfusion prior to 40 min of index ischemia and then 40 min of reperfusion. IPC resulted in 70% recovery of left ventricular developed pressure (LVDP) upon reperfusion and a small infarct size (10%). VPC23019 (VPC), a specific antagonist of S1P(1 and 3) G protein-coupled receptors (GPCRs), when present during preconditioning blocked protection afforded by two cycles of IPC. VPC also blocked preconditioning of isolated rat cardiac myocytes subjected to hypoxia-reoxygenation injury. Increased release of S1P from myocytes in response to IPC was also demonstrated. These data indicate that S1P is released from myocytes in response to IPC and protects by binding to S1P GPCRs. In the ex vivo heart, if a third cycle of IPC was added to increase release of endogenous mediators, then the need for any individual mediator (e.g., S1P) was diminished and VPC had little effect. The adenosine antagonist 8-(p-sulfophenyl)-theophylline (8-SPT) likewise inhibited protection by two cycles but not three cycles of IPC, but VPC plus 8-SPT inhibited protection by three cycles of IPC. Similar to IPC, IPOST induced by four postindex ischemia cycles of 15 s reperfusion-15 s ischemia resulted in 66% recovery of LVDP and a 7% infarct size. When VPC was present during postconditioning and reperfusion, LVDP only recovered by 26% and the infarct size increased to 27%. Adding an additional cycle of IPOST reduced the inhibitory effect of VPC and 8-SPT individually, but not their combined effect. These studies reveal that S1P is an important mediator of both IPC and IPOST that is released along with adenosine during each cycle of IPC or IPOST.

Sphingosine-1-Phosphate as a Potential Target for the Treatment of Myocardial Infarction

“…When present during pre-or postconditioning, the mixed S1P1/S1P3 receptor antagonist VPC23019 blocked protection afforded by either 2 cycles of preconditioning or 4 postindex ischemia cycles. 13 This antagonist also blocked preconditioning of isolated rat cardiac myocytes subjected to hypoxia-reoxygenation injury. The study also showed increased release of S1P from myocytes in response to preconditioning, suggesting that S1P released in response to preconditioning protects the heart by binding to membrane S1P receptors.…”

“…11 These enzymes seem to be an important source of endogenous S1P in the heart, and their appearance in mice as early as E8.5 suggests a key role in cardiac development. 12 S1P generation in the heart is upregulated in response to a transient ischemia, suggesting a beneficial contribution of the SPK-S1P axis to ischemic pre-and postconditioning 13 (…”

Sphingosine-1-phosphate as a mediator involved in development of fibrotic diseases

“…suggesting the contribution of the SphK-S1P axis to ischemic preconditioning and ischemic post-conditioning [26]. Mice heterozygous for deletion of the S1P-degradating enzyme S1P lyase gene and wild-type mice receiving an SPL inhibitor, which showed elevated S1P levels in both plasma and cardiac tissues, had reduced sensitivity to ischemia/reperfusion injury, raising a possibility of cardioprotection with an S1P lyase inhibitor in clinical settings [27].…”

Sphingosine-1-phosphate: distribution, metabolism and role in the regulation of cellular functions

“…Infarct size in SphK1-null mice appeared to be increased and the hearts of these mice demonstrated a poor response to ischemic preconditioning or postconditioning stimulus [54]. VPC23019 blocked cardioprotection in ex vivo rat hearts and in isolated cardiomyocytes [55].…”