sphingosine-1-phosphate and Heart-Failure

Heart failure (HF) is hallmarked by an increase in total peripheral resistance (TPR) that compensates for the drop in cardiac output. While initially allowing for the maintenance of mean arterial pressure at acceptable levels, the long-term upregulation of TPR is prone to compromise cardiac performance and tissue perfusion, and to ultimately accelerate disease progression. Augmented vasoconstriction of terminal arteries, the site of TPR regulation, is cooperatively driven by mechanisms such as: (i) endothelial dysfunction, (ii) increased sympathetic activity and (iii) enhanced pressure-induced myogenic responsiveness. Herein, we review emerging evidence that the increase in myogenic responsiveness is central to the long-term elevation of TPR in HF. On a molecular level, this augmented intrinsic response is governed by an activation of the tumor necrosis factor-α (TNF-α)/sphingosine-1-phosphate signaling axis in microvascular smooth muscle cells. The beneficial effect of TNF-α scavenging strategies on tissue perfusion in HF mouse models adds to the gaining momentum to revisit the use of anti-TNF-α treatment modalities in discrete HF patient populations.

Topics: Animals; Arterial Pressure; Cardiac Output; Cystic Fibrosis Transmembrane Conductance Regulator; Endothelium, Vascular; Heart Failure; Humans; Lysophospholipids; Muscle Development; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Signal Transduction; Sphingosine; Tumor Necrosis Factor-alpha; Vascular Resistance; Vasoconstriction

In the setting of obesity and type 2 diabetes mellitus, the ectopic disposition of lipids may be a cause of heart failure. Clinical studies have clearly shown a correlation between the accumulation of triglycerides and heart dysfunction. In this process, it is likely that there are also changes in the contents of sphingolipids. Sphingolipids are important structural and signaling molecules. One specific sphingolipid, ceramide, may cause cardiac dysfunction, whereas another, sphingosine 1-phosphate, is cardioprotective. In this review, the authors focus on the role of sphingolipids in the development and prevention of cardiac failure.

Topics: Apoptosis; Ceramides; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart Failure; Humans; Lipid Metabolism; Lysophospholipids; Myocytes, Cardiac; Sphingolipids; Sphingosine

In recent years, the role of sphingolipids in physiology and pathophysiology of the heart attracted much attention. Ceramide was found to be involved in the pathogenesis of cardiac dysfunction in animal models of ischemia/reperfusion injury, Type 2 diabetes and lipotoxic cardiomyopathy. On the other hand, another member of this lipid family, namely sphingosine-1-phosphate, has been shown to possess potent cardioprotective properties. This chapter provides a review of the role of ceramide and other bioactive sphingolipids in physiology and pathophysiology of the heart. We describe the role of PPARs and exercise in regulation of myocardial sphingolipid metabolism. We also summarize the present state of knowledge on the involvement of ceramide and sphingosine-1-phosphate in the development and prevention of ischemia/reperfusion injury of the heart. In the last section of this chapter we discuss the evidence for a role of ceramide in myocardial lipotoxicity.

Topics: Animals; Cardiomyopathies; Ceramides; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Exercise; Heart Failure; Humans; Lysophospholipids; Mice; Myocardial Reperfusion Injury; Myocardium; Obesity; Peroxisome Proliferator-Activated Receptors; Rats; Rats, Zucker; Receptors, Lysosphingolipid; Second Messenger Systems; Sphingolipids; Sphingosine

Chronic liver congestion reflecting right-sided heart failure (RHF), Budd-Chiari syndrome, or Fontan-associated liver disease (FALD) is involved in liver fibrosis and HCC. However, molecular mechanisms of fibrosis and HCC in chronic liver congestion remain poorly understood.. Here, we first demonstrated that chronic liver congestion promoted HCC and metastatic liver tumor growth using murine model of chronic liver congestion by partial inferior vena cava ligation (pIVCL). As the initial step triggering HCC promotion and fibrosis, gut-derived lipopolysaccharide (LPS) appeared to induce LSECs capillarization in mice and in vitro. LSEC capillarization was also confirmed in patients with FALD. Mitogenic factor, sphingosine-1-phosphate (S1P), was increased in congestive liver and expression of sphingosine kinase 1, a major synthetase of S1P, was increased in capillarized LSECs after pIVCL. Inhibition of S1P receptor (S1PR) 1 (Ex26) and S1PR2 (JTE013) mitigated HCC development and liver fibrosis, respectively. Antimicrobial treatment lowered portal blood LPS concentration, LSEC capillarization, and liver S1P concentration accompanied by reduction of HCC development and fibrosis in the congestive liver.. In conclusion, chronic liver congestion promotes HCC development and liver fibrosis by S1P production from LPS-induced capillarized LSECs. Careful treatment of both RHF and liver cancer might be necessary for patients with RHF with primary or metastatic liver cancer.

Topics: Animals; Carcinoma, Hepatocellular; Disease Models, Animal; Fibrosis; Heart Failure; Humans; Lipopolysaccharides; Liver Cirrhosis; Liver Neoplasms; Lysophospholipids; Mice; Receptors, Lysosphingolipid; Sphingosine; Vascular Diseases

Heart failure (HF) is among the main causes of death worldwide. Alterations of sphingosine-1-phosphate (S1P) signaling have been linked to HF as well as to target organ damage that is often associated with HF. S1P's availability is controlled by the cystic fibrosis transmembrane regulator (CFTR), which acts as a critical bottleneck for intracellular S1P degradation. HF induces CFTR downregulation in cells, tissues and organs, including the lung. Whether CFTR alterations during HF also affect systemic and tissue-specific S1P concentrations has not been investigated. Here, we set out to study the relationship between S1P and CFTR expression in the HF lung. Mice with HF, induced by myocardial infarction, were treated with the CFTR corrector compound C18 starting ten weeks post-myocardial infarction for two consecutive weeks. CFTR expression, S1P concentrations, and immune cell frequencies were determined in vehicle- and C18-treated HF mice and sham controls using Western blotting, flow cytometry, mass spectrometry, and qPCR. HF led to decreased pulmonary CFTR expression, which was accompanied by elevated S1P concentrations and a pro-inflammatory state in the lungs. Systemically, HF associated with higher S1P plasma levels compared to sham-operated controls and presented with higher S1P receptor 1-positive immune cells in the spleen. CFTR correction with C18 attenuated the HF-associated alterations in pulmonary CFTR expression and, hence, led to lower pulmonary S1P levels, which was accompanied by reduced lung inflammation. Collectively, these data suggest an important role for the CFTR-S1P axis in HF-mediated systemic and pulmonary inflammation.

Topics: Animals; Biomarkers; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Disease Susceptibility; Gene Expression; Heart Failure; Lung; Lysophospholipids; Mice; Organ Specificity; Pneumonia; Signal Transduction; Sphingosine; T-Lymphocyte Subsets

Sphingosine-1-phosphate (S1P) is a bioactive mediator in inflammation. Dysregulated S1P is demonstrated as a cause of heart failure (HF). However, the time-dependent and integrative role of S1P interaction with receptors in HF is unclear after myocardial infarction (MI). In this study, the sphingolipid mediators were quantified in ischemic human hearts. We also measured the time kinetics of these mediators post-MI in murine spleen and heart as an integrative approach to understand the interaction of S1P and respective S1P receptors in the transition of acute (AHF) to chronic HF (CHF). Risk-free 8-12 wk male C57BL/6 mice were subjected to MI surgery, and MI was confirmed by echocardiography and histology. Mass spectrometry was used to quantify sphingolipids in plasma, infarcted heart, spleen of mice, and ischemic and healthy human heart. The physiological cardiac repair was observed in mice with a notable increase of S1P quantity (pmol/g) in the heart and spleen significantly reduced in patients with ischemic HF. The circulating murine S1P levels were increased during AHF and CHF despite lowered substrate in CHF. The S1PR1 receptor expression was observed to coincide with the respective S1P quantity in mice and human hearts. Furthermore, selective S1P1 agonist limited inflammatory markers CCL2 and TNF-α and accelerated reparative markers ARG-1 and YM-1 in macrophages in the presence of Kdo2-Lipid A (KLA; potent inflammatory stimulant). This report demonstrated the importance of S1P/S1PR1 signaling in physiological inflammation during cardiac repair in mice. Alteration in these axes may serve as the signs of pathological remodeling in patients with ischemia.

Topics: Animals; Arginase; beta-N-Acetylhexosaminidases; Cells, Cultured; Chemokine CCL2; Heart Failure; Humans; Lectins; Lysophospholipids; Macrophages; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocytes, Cardiac; Regeneration; Sphingosine; Sphingosine-1-Phosphate Receptors; Spleen; Tumor Necrosis Factor-alpha

Accumulating evidence has confirmed that the expression of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) is downregulated in heart failure and cardiac allograft rejection. Although many SERCA2a-related genes and proteins involved in the regulation of myocardial Ca

Topics: Biomarkers; Female; Graft Rejection; Heart Diseases; Heart Failure; Heart Transplantation; Humans; Lysophospholipids; Male; Middle Aged; Myocardium; Myocytes, Cardiac; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sphingosine

Acute heart failure (AHF) is a burden disease, with high mortality and re-hospitalisations. Using an ex-vivo model of AHF, we have previously reported that sphingosine-1-phosphate (S1P) confers cardioprotection. However, the mechanisms remain to be elucidated. In the present study, we aimed to examine the role of the cardioprotective signal transducer and activator of transcription 3 (STAT3) in S1P mediated improved functional recovery in AHF.. Isolated hearts from male Long-Evans rats were subjected to hypotensive AHF for 35 min followed by a recovery phase of 30 min (n ≥ 4/group). S1P (10 nM) was given during either the hypotensive or the recovery phase with/without an inhibitor of STAT3, AG490. Functional parameters were recorded throughout the experiment.. Following an AHF insult, S1P, given during the recovery phase, improved the heart rate (HR) compared to the control (175.2 ± 30.7 vs. 71.6 ± 27.4 beats per minute (BPM); p < 0.05), with no changes in the left ventricular developed pressure. This effect was associated with an increase in phosphorylated STAT3 levels in the nucleus. Addition of AG490 with S1P abolished the cardioprotective effect of S1P (42.3 ± 17.1 vs. 148.8 ± 26.4 BPM for S1P; p < 0.05).. Our data suggest that S1P protects in an ex-vivo rat heart model of AHF by activation of STAT3 and provide further evidence for the usage of S1P as a potential therapy in patients suffering from AHF.

Topics: Acute Disease; Animals; Blood Pressure; Cardiotonic Agents; Heart Failure; Heart Rate; In Vitro Techniques; Lysophospholipids; Male; Phosphorylation; Rats; Rats, Long-Evans; Sphingosine; STAT3 Transcription Factor; Tyrphostins; Ventricular Dysfunction, Left

High-density lipoprotein (HDL) has been shown to confer cardiovascular protection in clinical and epidemiologic studies. Emerging evidence suggests that many of the cardioprotective functions of HDL may be due to the phospholipid sphingosine-1-phosphate (S1P).. HDL-S1P binds to S1P receptors in the heart, activating PI3K/Akt signaling and myocyte survival. PI3K/Akt is a classic signaling modulator of autophagy. Excessive autophagy due to cell death and cardiomyocyte loss may contribute to impaired heart function during pressure overload-induced heart failure. Therefore, we hypothesize that HDL-S1P may suppress excessive autophagy of cardiomyocytes through activation of PI3K/Akt signaling. Further, reconstituted HDL (including S1P) may protect heart function during pressure overload-induced heart failure.. We will design the following experiments to test this hypothesis. (1) We will treat cells and mice with PI-3 kinase inhibitors to examine if HDL-S1P downregulates expression of Autophagy-related genes (ATGs) and proteins via activation of PI3K/Akt signaling. (2) We will use siRNA against S1P receptors or inhibitors of S1P receptors to determine which types of S1P receptors participate in this mechanism. (3) We will also examine if reconstituted HDL (including S1P) improves heart function during pressure overload-induced heart failure by suppressing excessive autophagy of cardiomyocytes through activation of PI3K/Akt signaling.. Understanding the autophagy signaling pathway modulated by HDL-S1P will make a major contribution to the field by identifying a novel mechanism for cardiovascular protection of high-density lipoprotein. Further, using reconstituted HDL to improve heart function would provide a novel therapeutic approach for pressure overload-induced heart failure.

Topics: Animals; Autophagy; Cardiotonic Agents; Coronary Disease; Heart Failure; Humans; Lipoproteins, HDL; Lysophospholipids; Myocytes, Cardiac; Sphingosine

Topics: Animals; Cystic Fibrosis Transmembrane Conductance Regulator; Down-Regulation; Heart Failure; Lysophospholipids; Signal Transduction; Sphingosine; Tumor Necrosis Factor-alpha

Sphingosine-1-phosphate (S1P) signaling is a central regulator of resistance artery tone. Therefore, S1P levels need to be tightly controlled through the delicate interplay of its generating enzyme sphingosine kinase 1 and its functional antagonist S1P phosphohydrolase-1. The intracellular localization of S1P phosphohydrolase-1 necessitates the import of extracellular S1P into the intracellular compartment before its degradation. The present investigation proposes that the cystic fibrosis transmembrane conductance regulator transports extracellular S1P and hence modulates microvascular S1P signaling in health and disease.. In cultured murine vascular smooth muscle cells in vitro and isolated murine mesenteric and posterior cerebral resistance arteries ex vivo, the cystic fibrosis transmembrane conductance regulator (1) is critical for S1P uptake; (2) modulates S1P-dependent responses; and (3) is downregulated in vitro and in vivo by tumor necrosis factor-α, with significant functional consequences for S1P signaling and vascular tone. In heart failure, tumor necrosis factor-α downregulates the cystic fibrosis transmembrane conductance regulator across several organs, including the heart, lung, and brain, suggesting that it is a fundamental mechanism with implications for systemic S1P effects.. We identify the cystic fibrosis transmembrane conductance regulator as a critical regulatory site for S1P signaling; its tumor necrosis factor-α-dependent downregulation in heart failure underlies an enhancement in microvascular tone. This molecular mechanism potentially represents a novel and highly strategic therapeutic target for cardiovascular conditions involving inflammation.

Topics: Animals; Brain; Cells, Cultured; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Down-Regulation; Heart Failure; In Vitro Techniques; Lung; Lysophospholipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocardium; Signal Transduction; Sphingosine; Tumor Necrosis Factor-alpha

Heart failure is associated with neurological deficits, including cognitive dysfunction. However, the molecular mechanisms underlying reduced cerebral blood flow in the early stages of heart failure, particularly when blood pressure is minimally affected, are not known.. Using a myocardial infarction model in mice, we demonstrate a tumor necrosis factor-α (TNFα)-dependent enhancement of posterior cerebral artery tone that reduces cerebral blood flow before any overt changes in brain structure and function. TNFα expression is increased in mouse posterior cerebral artery smooth muscle cells at 6 weeks after myocardial infarction. Coordinately, isolated posterior cerebral arteries display augmented myogenic tone, which can be fully reversed in vitro by the competitive TNFα antagonist etanercept. TNFα mediates its effect via a sphingosine-1-phosphate (S1P)-dependent mechanism, requiring sphingosine kinase 1 and the S1P(2) receptor. In vivo, sphingosine kinase 1 deletion prevents and etanercept (2-week treatment initiated 6 weeks after myocardial infarction) reverses the reduction of cerebral blood flow, without improving cardiac function.. Cerebral artery vasoconstriction and decreased cerebral blood flow occur early in an animal model of heart failure; these perturbations are reversed by interrupting TNFα/S1P signaling. This signaling pathway may represent a potential therapeutic target to improve cognitive function in heart failure.

Topics: Animals; Cerebral Arteries; Etanercept; Heart Failure; Immunoglobulin G; Lysophospholipids; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Muscle Development; Muscle, Smooth, Vascular; Phosphotransferases (Alcohol Group Acceptor); Receptors, Lysosphingolipid; Receptors, Tumor Necrosis Factor; Regional Blood Flow; Signal Transduction; Sphingosine; Tumor Necrosis Factor-alpha; Vasoconstriction

Mechanisms underlying vasomotor abnormalities and increased peripheral resistance exacerbating heart failure (HF) are poorly understood.. To explore the role and molecular basis of myogenic responses in HF.. 10 weeks old C57Bl6 mice underwent experimental myocardial infarction (MI) or sham surgery. At 1 to 12 weeks postoperative, mice underwent hemodynamic studies, mesenteric, cerebral, and cremaster artery perfusion myography and Western blot. Organ weights and hemodynamics confirmed HF and increased peripheral resistance after MI. Myogenic responses, ie, pressure-induced vasoconstriction, were increased as early as 1 week after MI and remained elevated. Vasoconstrictor responses to phenylephrine were decreased 1 week after MI, but not at 2 to 6 weeks after MI, whereas those to endothelin (ET)-1 and sphingosine-1-phosphate (S1P) were increased at all time points after MI. An antagonist (JTE-013) for the most abundant S1P receptor detected in mesenteric arteries (S1P(2)R) abolished the enhanced myogenic responses of HF, with significantly less effect on controls. Mice with genetic absence of sphingosine-kinases or S1P(2)R (Sphk1(-/-); Sphk1(-/-)/Sphk2(+/-); S1P(2)R(-/-)) did not manifest enhanced myogenic responses after MI. Mesenteric arteries from HF mice exhibited increased phosphorylation of myosin light chain, with deactivation of its phosphatase (MLCP). Among known S1P-responsive regulators of MLCP, GTP-Rho levels were unexpectedly reduced in HF, whereas levels of activated p38 MAPK and ERK1/2 (extracellular signal-regulated kinase 1/2) were increased. Inhibiting p38 MAPK abolished the myogenic responses of animals with HF, with little effect on controls.. Rho-independent p38 MAPK-mediated deactivation of MLCP underlies S1P/S1P(2)R-regulated increases in myogenic vasoconstriction observed in HF. Therapeutic targeting of these findings in HF models deserves study.

Topics: Animals; Coronary Circulation; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Heart Failure; Lysophospholipids; Male; MAP Kinase Signaling System; Mesenteric Arteries; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Myocardial Infarction; Myosin Light Chains; p38 Mitogen-Activated Protein Kinases; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors; Vascular Resistance; Vasoconstriction

Topics: Animals; Heart Failure; Heart Rate; Heart Ventricles; Lysophospholipids; Myocardial Contraction; Myocardial Reperfusion Injury; Rats; Signal Transduction; Sphingosine