Cardioprotection in ischemia/reperfusion injury: spotlight on sphingosine-1-phosphate and bradykinin signalling

Abstract

Complex signal-transduction cascades are known to be involved in regulating cardiomyocyte function, death and survival during acute cardiac ischemia-reperfusion process, but detailed survival signalling pathways are not clear. This review presents and discusses the recent findings bearing upon the evidence on the cardioprotective effect of sphingosine-1-phosphate (S1P) and bradykinin in acute cardiac ischemia-reperfusion and underlying signalling mechanisms, particularly, through activation of P21 activated kinase.

Fig. 1

Expression profiles of S1P receptor mRNAs in rat heart tissue. A: Expression of regionally distributed MLCA1 and MLC2V in the atria, SAN and ventricle tissues. B: Expression profile of S1P receptors mRNAs in sinoatrial node tissue, in atrial tissue and in ventricular tissue. Means ± SEM (n = 7) shown. *p < 0.05; One way ANOVA. LV, left ventricle; RA, right atrium; SAN, sinoatrial node; MLC1A, atrial myosin light chain gene; MLC2V, ventricular myosin light chain gene.

Fig. 2

The effect of FTY720 on rhythm disturbance induced by ischemia/reperfusion in rat heart preparations. ECG recordings from Langendorff perfused heart in the presence and absence of FTY720. A_B: in the absence of FTY720, RR interval, P–R, QRS and QT intervals were significantly increased during ischemia and reperfusion, but in the presence of FTY720, RR interval, P–R, QRS and QT intervals were not significantly different than those during the control condition or during ischemia and reperfusion. Both tachycardia-related (ectopic beats, non-sustained and sustained episodes of ventricular tachycardia (VT) and ventricular fibrillation (VF)) and bradycardia-related (sinus bradycardia, sinus pause, sinus arrest, and A–V conduction block) arrhythmic events were frequently observed after 5–10 min in the presence of ischemic conditions. C: FTY720 greatly reduced the occurrence of premature ventricular beats, VT and sinus bradycardia as well as A-V conduction block caused by I/R injury.

Fig. 3

Previous studies of ours have indicated that Pak1 executes its anti-adrenergic function in the heart through activation of phosphatase PP2A. Both Pak1 and Akt may play a significant role in S1P₁ and S1P₃ mediated cardioprotective effects during cardiac ischemia and reperfusion. Pak1 is not only involved in regulation of myofilament activity, but also regulates activities of ion channels which are directly related to ischemia/reperfusion induced arrhythmia. It remains unclear if Pak1 and Akt are related to other cardioprotective signals, such as PI3 kinase, eNOS etc. The inhibitory G protein is a key upstream signal for Pak1 in cardiomyocytes. Abbreviations: LCC–L-type Ca channel; PLB–phospholamban; cTnI–cardiac troponin I; MyBP-C–myosin binding protein C; SK-1–sphingosine-1 kinase, S1P–sphingosine-1-phosphate.