Opposing Roles of S1P3 Receptors in Myocardial Function

Abstract

Sphingosine-1-phosphate (S1P) is a lysophospholipid mediator with diverse biological function mediated by S1P1–5 receptors. Whereas S1P was shown to protect the heart against ischemia/reperfusion (I/R) injury, other studies highlighted its vasoconstrictor effects. We aimed to separate the beneficial and potentially deleterious cardiac effects of S1P during I/R and identify the signaling pathways involved. Wild type (WT), S1P2-KO and S1P3-KO Langendorff-perfused murine hearts were exposed to intravascular S1P, I/R, or both. S1P induced a 45% decrease of coronary flow (CF) in WT-hearts. The presence of S1P-chaperon albumin did not modify this effect. CF reduction diminished in S1P3-KO but not in S1P2-KO hearts, indicating that in our model S1P3 mediates coronary vasoconstriction. In I/R experiments, S1P3 deficiency had no influence on postischemic CF but diminished functional recovery and increased infarct size, indicating a cardioprotective effect of S1P3. Preischemic S1P exposure resulted in a substantial reduction of postischemic CF and cardiac performance and increased the infarcted area. Although S1P3 deficiency increased postischemic CF, this failed to improve cardiac performance. These results indicate a dual role of S1P3 involving a direct protective action on the myocardium and a cardiosuppressive effect due to coronary vasoconstriction. In acute coronary syndrome when S1P may be released abundantly, intravascular and myocardial S1P production might have competing influences on myocardial function via activation of S1P3 receptors.

Angiotensin II-Induced Cardiac Effects Are Modulated by Endocannabinoid-Mediated CB1 Receptor Activation

“…However, in our experimental setting, the negative functional effects on the heart are suggested to be an indirect consequence of decreased coronary perfusion. In our system, interventions, which decrease CF without having a direct influence on cardiac cells (e.g., mechanical compression of the inflow line ( Figure 3 F), or vasoconstrictors with mere vascular effects [ 33 ]), normally elicit a decrease of the same magnitude in contractile function. In the current study, CF decreased and remained lower than control throughout the Ang II administration ( Figure 3 A); however, this was accompanied by only a moderate and transient decrease in contractile performance ( Figure 3 B–D).…”

“…The isolated hearts were cannulated and perfused using a gravitational Langendorff apparatus (Experimetria Ltd., Budapest, Hungary) at constant, 70 mmHg pressure with a modified Krebs–Henseleit buffer. A detailed description of the perfusion and methodology of measuring hemodynamic parameters in a Langendorff-perfused heart preparation was given previously [ 33 , 34 , 35 ]. Briefly, left ventricular pressure (LVP) was recorded using a fluid-filled balloon catheter introduced into the ventricle and connected to a pressure gauge (Experimetria Ltd., Budapest, Hungary), whereas coronary flow (CF) was continuously monitored with a transit-time flow probe placed into the inflow line (Transonic 2-PXN flow probe, TS410-tubing flow module Transonic Systems Inc., Ithaca, NY, USA) [ 33 , 34 , 35 ].…”

“…Left ventricular developed pressure (LVDevP) was calculated as the difference between peak systolic and minimum diastolic pressures. The positive and negative maximum values of the first derivative of the LVP (+dLVP/dt max , −dLVP/dt max ) were determined as indices of left ventricular contractile and lusitropic performance, respectively [ 33 , 34 , 35 ].…”

“…After cannulation of the isolated heart, a 30-min equilibration period was allowed. Afterward, baseline data were recorded, and the respective substances or their vehicles were infused as described previously [ 33 ].…”

Role of sphingosine 1-phosphate (S1P) in sepsis-associated intestinal injury

“…In addition, S1P has been shown to have contractile effects in arteries of a variety of animals (86), angiotensin II (AngII) treatment leads to hypertension (BP) associated with increased plasma S1P and circulating T cell counts, and SphK2 activity is critical for AngII-induced lymphocyte trafficking. Moreover, the dysregulation of SphK2 expression is related to the thrombotic inflammatory phenotype of microvessels and the functional changes of small resistance arteries, leading to the development of hypertension (87).…”