Combined sphingosine, S1P and ischemic postconditioning rescue the heart after protracted ischemia

Abstract

Both sphingosine and sphingosine 1-phosphate (S1P) were able to protect the ex vivo rat heart from ischemia reperfusion injury when added to the perfusion medium at the time of reperfusion after a 40 min ischemia (postconditioning). Inhibitor studies revealed distinct mechanisms of protection, with S1P employing a G-protein coupled receptor pathway and sphingosine a cyclic nucleotide dependent protein kinase pathway. However, both restored ischemia-induced depletion of phospho-AKT. Extending the ischemia to 75 min reduced protection by both S1P and sphingosine, but protection could be enhanced by employing them in combination. Extending the time of ischemia further to 90 min almost eliminated cardioprotection by S1P or sphingosine; and their combination gave only modest protection. However, when S1P plus sphingosine was combined with a novel ramped ischemic postconditioning regimen, left ventricle developed pressure recovered by 66% and there was only a 6% infarct size. The data indicate that detrimental changes are accumulating during protracted ischemia but for up to 90 min this damage is not irreversible and hearts can still recover with proper treatment.

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…Although many postconditioning interventions are affected by age, pharmacologic postconditioning with sphingosine reduced infarct size to the same extent in young and aged rat hearts (Vessey et al, 2009). Blockade of PKG or PKA attenuated the cardioprotection by sphingosine, suggesting that the cyclic nucleotide-dependent signaling pathway utilized by sphingosine remains unaffected by age (Vessey et al, 2008a(Vessey et al, ,b, 2009.…”

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

“…When used in pre-or post-conditioning ex vivo rat heart models, both compounds provided more than 75% recovery of left ventricular developed pressure during reperfusion and a reduction in size of infarct from 45% to less than 8% after 40-min ischemia. Combined application of both compounds provided an enhancement of the protective effect against ischemia for up to 90 min and a combination of S1P, sphingosine, and a ramped ischemic postconditioning regimen gave an additional heart protective effect [81]. Bielawska et al [82] were the first to demonstrate in vitro and in vivo that ceramide signaling can be involved in ischemia/reperfusion-induced cardiomyocytes apoptosis.…”

“…The molecular cardioprotective mechanisms used by S1P and огляДи sphingosine are different [53]. S1P uses a G-protein coupled receptor pathway while sphingosine acts via a cyclic nucleotide-dependent protein kinase pathway [81]. Ethanolamine, which is a S1P and anandamide (N-arachidonoylethanolamine, an endogenous cannabinoid neurotransmitter) biodegradation product, also appeared to possess cardioprotective properties in an isolated heart ischemia/reperfusion mouse model (30 min ischaemia/2 h reperfusion) [84].…”

Les récepteurs de la sphingosine 1-phosphate

“…In vitro, la S1P inhibe l'apoptose des cardiomyocytes en réponse à l'hypoxie, et ce par l'activation du S1P 1 car les effets de la S1P sont mimés par l'agoniste SEW2871 et de faibles concentrations de FTY720 [18]. Dans des modèles animaux d'I-R, l'ajout de S1P reproduit les effets favorables du préconditionnement, c'est-à-dire de brefs épisodes d'I-R, mais aussi du postconditionnement par un mécanisme dépendant du S1P 1 et/ou du S1P3, car le VPC23019 bloque ces effets [19]. Concernant le possible rôle du S1P 1 des cardiomyocytes dans l'effet protecteur de la S1P, des observations discordantes ont été rapportées, suggérant plutôt un rôle combiné des S1P 2 et S1P 3 sur la base de l'aggravation des dommages cardiaques chez les souris doublement délétées pour ces récepteurs [20], leur délétion unique étant sans conséquence.…”