cardiovascular-agents and sphingosine-1-phosphate

Atherosclerosis is the major cause of mortality in the developed countries. Although presently known risk factors have some predictive value for the disease, a major part of the variability in this process remains unexplained. It is extremely important to find new approaches for better understanding of the disease and for treating it. Exploration of the sphingolipid metabolism is one of these approaches. Sphingolipids are a large class of lipids with structural and signaling functions. Recent researches indicated that these lipids play important roles in the development of atherosclerosis. In this chapter, we summarized the major findings in the field.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Drug Design; Humans; Lysophospholipids; Molecular Targeted Therapy; Signal Transduction; Sphingolipids; Sphingomyelins; Sphingosine

Sphingosine-1-phosphate (S1P) regulates important functions in cardiac and vascular homeostasis. It has been implied to play causal roles in the pathogenesis of many cardiovascular disorders such as coronary artery disease, atherosclerosis, myocardial infarction, and heart failure. The majority of S1P in plasma is associated with high-density lipoproteins (HDL), and their S1P content has been shown to be responsible, at least in part, for several of the beneficial effects of HDL on cardiovascular risk. The attractiveness of S1P-based drugs for potential cardiovascular applications is increasing in the wake of the clinical approval of FTY720, but answers to important questions on the effects of S1P in cardiovascular biology and medicine must still be found. This chapter focuses on the current understanding of the role of S1P and its receptors in cardiovascular physiology, pathology, and disease.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Drug Design; Hemodynamics; Humans; Lipoproteins, HDL; Lysophospholipids; Signal Transduction; Sphingosine

Upon various stimuli, cells metabolize sphingomyelin from the cellular plasma membrane to form sphingosylphosphorylcholine (SPC) or ceramide. The latter can be further metabolized to sphingosine and then sphingosine-1-phosphate (S1P). Apart from local formation, S1P and SPC are major constituents of blood plasma. All four sphingomyelin metabolites (SMM) can act upon intracellular targets, and at least S1P and probably also SPC can additionally act upon G-protein-coupled receptors. While the molecular identity of the SPC receptors remains unclear, several subtypes of S1P receptors have been cloned and their distribution in cardiovascular tissues is described. In the heart SMM can alter intracellular Ca(2+) release, particularly via the ryanodine receptor, and conductance of various ion channels in the plasma membrane, particularly I(K(Ach)). While the various SMM differ somewhat in their effects, the above alterations of ion homeostasis result in reduced cardiac function in most cases, and ceramide and/or sphingosine may be the mediators of the negative inotropic effects of tumour necrosis factor. In the vasculature, SMM mainly act as acute vasoconstrictors in most vessels, but ceramide can be a vasodilator. SMM-induced vasoconstriction involves mobilization of Ca(2+) from intracellular stores, influx of extracellular Ca(2+) via L-type channels and activation of a rho-kinase. Extended exposure to SMM, particularly S1P, promotes several stages of the angiogenic process like endothelial cell activation, migration, proliferation, tube formation and vascular maturation. We propose that SMM are an important class of endogenous modulators of cardiovascular function.

Topics: Animals; Cardiovascular Agents; Cardiovascular System; Humans; Lysophospholipids; Receptors, Lysosphingolipid; Sphingomyelins; Sphingosine

Anandamide and sphingosine-1-phosphate (S1P) both regulate vascular tone in a variety of vessels. This study aimed to examine the mechanisms involved in the regulation of coronary vascular tone by anandamide and S1P, and to determine whether any functional interaction occurs between these receptor systems.. Mechanisms used by anandamide and S1P to regulate rat coronary artery (CA) reactivity were investigated using wire myography. Interactions between S1P and the cannabinoid (CB)(2) receptor were determined using human embryonic kidney 293 (HEK293) cells that stably over-express recombinant CB(2) receptor.. Anandamide and S1P induced relaxation of the rat CA. CB(2) receptor antagonists attenuated anandamide-induced relaxation, while S1P-mediated relaxation was dependent on the vascular endothelium and S1P(3). Anandamide treatment resulted in an increase in the phosphorylation of sphingosine kinase-1 within the CA. Conversely, anandamide-mediated relaxation was attenuated by inhibition of sphingosine kinase. Moreover, S1P(3), specifically within the vascular endothelium, was required for anandamide-mediated vasorelaxation. In addition to this, S1P-mediated relaxation was also reduced by CB(2) receptor antagonists and sphingosine kinase inhibition. Further evidence that S1P functionally interacts with the CB(2) receptor was also observed in HEK293 cells over-expressing the CB(2) receptor.. In the vascular endothelium of rat CA, anandamide induces relaxation via a mechanism requiring sphingosine kinase-1 and S1P/S1P(3). In addition, we report that S1P may exert some of its effects via a CB(2) receptor- and sphingosine kinase-dependent mechanism, where subsequently formed S1P may have privileged access to S1P(3) to induce vascular relaxation.

Topics: Animals; Arachidonic Acids; Calcium Channel Blockers; Cardiovascular Agents; Cell Line; Coronary Vessels; Dronabinol; Endocannabinoids; Humans; Indoles; Indomethacin; Lysophospholipids; Male; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Sphingosine; Vasodilation

Ethanolamine is a biogenic amine found naturally in the body as part of membrane lipids and as a metabolite of the cardioprotective substances, sphingosine-1-phosphate (S1P) and anandamide. In the brain, ethanolamine, formed from the breakdown of anandamide protects against ischaemic apoptosis. However, the effects of ethanolamine in the heart are unknown. Signal transducer and activator of transcription 3 (STAT-3) is a critical prosurvival factor in ischaemia/reperfusion (I/R) injury. Therefore, we investigated whether ethanolamine protects the heart via activation of STAT-3. Isolated hearts from wildtype or cardiomyocyte specific STAT-3 knockout (K/O) mice were pre-treated with ethanolamine (Etn) (0.3 mmol/L) before I/R insult. In vivo rat hearts were subjected to 30 min ischaemia/2 h reperfusion in the presence or absence of 5 mg/kg S1P and/or the FAAH inhibitor, URB597. Infarct size was measured at the end of each protocol by triphenyltetrazolium chloride staining. Pre-treatment with ethanolamine decreased infarct size in isolated mouse or rat hearts subjected to I/R but this infarct sparing effect was lost in cardiomyocyte specific STAT-3 deficient mice. Pre-treatment with ethanolamine increased nuclear phosphorylated STAT-3 [control 0.75 ± 0.08 vs. Etn 1.50 ± 0.09 arbitrary units; P < 0.05]. Our findings suggest a novel cardioprotective role for ethanolamine against I/R injury via activation of STAT-3.

Topics: Amidohydrolases; Animals; Benzamides; Carbamates; Cardiovascular Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Ethanolamine; Janus Kinases; Lysophospholipids; Male; Mice; Mice, Knockout; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphorylation; Rats; Rats, Wistar; Sphingosine; STAT3 Transcription Factor; Tyrphostins

Edaravone is a potent scavenger of hydroxyl radicals and is quite successful in patients with acute cerebral ischemia, and several organ-protective effects have been reported. Treatment of human microvascular endothelial cells with edaravone (1.5 microM) resulted in the enhancement of transmonolayer electrical resistance coincident with cortical actin enhancement and redistribution of focal adhesion proteins and adherens junction proteins to the cell periphery. Edaravone also induced small GTPase Rac activation and focal adhesion kinase (FAK; Tyr(576)) phosphorylation associated with sphingosine-1-phosphate receptor type 1 (S1P(1)) transactivation. S1P(1) protein depletion by the short interfering RNA technique completely abolished edaravone-induced FAK (Tyr(576)) phosphorylation and Rac activation. This is the first report of edaravone-induced endothelial barrier enhancement coincident with focal adhesion remodeling and cytoskeletal rearrangement associated with Rac activation via S1P(1) transactivation. Considering the well-established endothelial barrier-protective effect of S1P, endothelial barrier enhancement as a consequence of S1P(1) transactivation may at least partly be the potent mechanisms for the organ-protective effect of edaravone and is suggestive of edaravone as a therapeutic agent against systemic vascular barrier disorder.

Topics: Actins; Adherens Junctions; Antipyrine; Capillary Permeability; Cardiovascular Agents; Cells, Cultured; Edaravone; Electric Impedance; Endothelial Cells; Focal Adhesion Kinase 1; Focal Adhesions; Free Radical Scavengers; Humans; Lysophospholipids; Microcirculation; Paxillin; Phosphorylation; rac GTP-Binding Proteins; Receptors, Lysosphingolipid; RNA Interference; RNA, Small Interfering; Signal Transduction; Sphingosine; Time Factors

1. Activation of muscarinic K+ current (IK(ACh)) by sphingosine-1-phosphate (Sph-1-P) was studied in isolated cultured guinea-pig atrial myocytes using whole-cell voltage clamp. 2. Sph-1-P caused activation of IK(ACh) with an EC50 of 1.2 nM. The maximal current that could be activated by Sph-1-P amounted to about 90% of the IK(ACh) caused by a saturating concentration of acetylcholine (ACh, 10 microM). Sphingosine (1 microM), which can mimic the signalling effects of Sph-1-P in other cells, failed to cause measurable activation of IK(ACh). 3. IK(ACh) activation by Sph-1-P was completely suppressed in cells treated with pertussis toxin. 4. Desensitization of muscarinic receptors by pre-incubation of the cells with carbachol did not affect the response to Sph-1-P; likewise, pre-incubation of the cells with Sph-1-P resulted in a reduced sensitivity to the phospholipid but not to ACh. In contrast, pre-incubation with either Sph-1-P or a serum phospholipid previously described as activating atrial IK(ACh) resulted in reduced sensitivity to both phospholipids. 5. It is concluded that activation of IK(ACh) by Sph-1-P in atrial myocytes is induced by binding to a novel G protein-coupled phospholipid receptor.

Topics: Acetylcholine; Adenosine; Animals; Biotransformation; Cardiovascular Agents; Female; GTP-Binding Proteins; Guinea Pigs; Heart; In Vitro Techniques; Lysophospholipids; Male; Membrane Potentials; Muscarinic Agonists; Myocardium; Patch-Clamp Techniques; Phospholipids; Potassium Channels; Signal Transduction; Sphingosine