Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes

Abstract

Landeen LK, Dederko DA, Kondo CS, Hu BS, Aroonsakool N, Haga JH, Giles WR. Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes. Am J Physiol Heart Circ Physiol 294: H736-H749, 2008. First published November 16, 2007 doi:10.1152/ajpheart.00316.2007.-Sphingosine-1-phosphate (S1P) induces a transient bradycardia in mammalian hearts through activation of an inwardly rectifying K ϩ current (IK ACh ) in the atrium that shortens action potential duration (APD) in the atrium. We have investigated probable mechanisms and receptor-subtype specificity for S1P-induced negative inotropy in isolated adult mouse ventricular myocytes. Activation of S1P receptors by S1P (100 nM) reduced cell shortening by ϳ25% (vs. untreated controls) in fieldstimulated myocytes. S1P 1 was shown to be involved by using the S1P 1-selective agonist SEW2871 on myocytes isolated from S1P3-null mice. However, in these myocytes, S1P 3 can modulate a somewhat similar negative inotropy, as judged by the effects of the S1P 1 antagonist VPC23019. Since S1P1 activates Gi exclusively, whereas S1P 3 activates both Gi and Gq, these results strongly implicate the involvement of mainly G i. Additional experiments using the IK ACh blocker tertiapin demonstrated that IK ACh can contribute to the negative inotropy following S1P activation of S1P 1 (perhaps through Gi␤␥ subunits). Mathematical modeling of the effects of S1P on APD in the mouse ventricle suggests that shortening of APD (e.g., as induced by I K ACh ) can reduce L-type calcium current and thus can decrease the intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) transient. Both effects can contribute to the observed negative inotropic effects of S1P. In summary, these findings suggest that the negative inotropy observed in S1P-treated adult mouse ventricular myocytes may consist of two distinctive components: 1) one pathway that acts via G i to reduce L-type calcium channel current, blunt calcium-induced calcium release, and decrease [Ca 2ϩ ]i; and 2) a second pathway that acts via Gi to activate IK ACh and reduce APD. This decrease in APD is expected to decrease Ca 2ϩ influx and reduce [Ca 2ϩ ]i and myocyte contractility.calcium; contraction; cell shortening; inhibitory G protein; acetylcholine-sensitive potassium; myocyte SPHINGOSINE-1-PHOSPHATE (S1P) is a biologically active, cell membrane-associated sphingolipid that binds with high affinity to five distinct G-coupled protein receptor isoforms (S1P 1-5 ). S1P 1 has been detected in abundance in neonatal rat cardiomyocytes (39). In these cells, exposure to S1P (500 nM) results in an initial negative inotropic effect (reduction of systolic calcium). However, this may be followed by calcium overload (increased diastolic calcium) and then a cessation of contractility. In isolated atrial myocytes, S1P has been shown to activate a weakly inwardly rectifying potassium (K ϩ ) current. This K ϩ conductance is very similar to the K ϩ current activated by ACh (I K ACh ). Activation of this current can shorte...

Disruption of Protein Kinase A Localization Using a Trans-activator of Transcription (TAT)-conjugated A-kinase-anchoring Peptide Reduces Cardiac Function

“…A custom designed electrode was used for field stimulation of each ventricular myocyte. The maximal rates of contraction and relaxation were calculated after the primary data had been "smoothed" with 3 point averaging to reduce high frequency noise (31).…”

Effect of sphingosine-1-phosphate on L-type calcium current and Ca2+ transient in rat ventricular myocytes

“…Interestingly, the S1P1 receptor agonist, SEW2871, was found as efficacious as S1P at antagonising ISO-stimulated contractility, while the administration of the S1P1 ? 3 receptor antagonist, VPC23019, blocked the negative inotropic actions of SEW2871, which was observed in S1P3 receptor knockout cardiac myocytes [9]. These findings suggest that the S1P1 receptor may be the primary receptor that mediates the negative inotropic effects of S1P in ventricular myocytes; while the S1P3 receptor may have only a small contribution.…”

“…Evidence suggests that the cardio-pulmonary system has the highest S1P1, S1P2, and S1P3 receptors expression [5,6], whereas the lymphatic system [7] and the central nervous system [8] express mainly S1P4 and S1P5 receptors, respectively. Animal studies suggest that the administration of S1P may lead to a decrease in cell shortening as well as antagonising isoproterenol (ISO)-induced increases in cAMP and positive inotropy [9]. Interestingly, the S1P1 receptor agonist, SEW2871, was found as efficacious as S1P at antagonising ISO-stimulated contractility, while the administration of the S1P1 ?…”

Effect of sphingosine-1-phosphate and myoblast transplantation on rat acute myocardial infarction

“…S1P is mediated by a subfamily of G protein-coupled receptors encoded by endothelial differentiation genes (Edgs). In the myocardium, Edg-3 and Edg-5 receptors are expressed at high levels (Landeen et al, 2008). S1P can protect myocardial cells by binding to Edg-3 and Edg-5 receptors, which activates Akt and reduces ischemia/reperfusion injury (Means et al, 2007).…”