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1.
Pregnancy Hypertens ; 19: 100-105, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31927322

RESUMO

OBJECTIVES: Ceramide is a sphingolipid with anti-angiogenic and pro-apoptotic properties that has shown to be increased in plasma of women with pre-eclampsia. We aimed to compare plasma and placental sphingolipid content among normotensive pregnant women and pre-eclamptic women with and without HELLP syndrome and we aimed to assess whether ceramide is related to hypertension and proteinuria in pre-eclampsia. STUDY DESIGN: Case-control study. Participants were recruited from the Department of Obstetrics at the Academic Medical Center in Amsterdam, The Netherlands. In total 48 pregnant women were included: 24 with pre-eclampsia and 24 normotensive controls. Of the 24 pre-eclamptic women, 11 had HELLP syndrome. MAIN OUTCOME MEASURES: Plasma and placental ceramide content and correlation with blood pressure and protein excretion in pre-eclampsia. RESULTS: Total plasma, but not placental, ceramide was higher in pre-eclamptic women with HELLP syndrome (11200 95% CI 9531-12870 nmol/ml, n = 11) compared to pre-eclamptic women without HELLP (7413 95% CI 5928-8898 nmol/ml, n = 13, p < 0.001) and normotensive pregnant women (7404 95% CI 6695-8112 nmol/ml, n = 24, p < 0.001). Maternal circulating ceramide levels were strongly associated with proteinuria (r = 0.621, n = 24, p = 0.001) in pre-eclamptic women and inversely correlated with gestational age at delivery (r = 0.771, p < 0.01) in pre-eclamptic women with HELLP syndrome. Plasma ceramide was not correlated with blood pressure. CONCLUSION: Plasma but not placental ceramide content is increased in women with pre-eclampsia and HELLP syndrome. The strong positive correlation with proteinuria and the inverse correlation with gestational age at delivery indicate that excess plasma ceramide may contribute to the pathophysiology of pre-eclampsia and HELLP.


Assuntos
Ceramidas/metabolismo , Síndrome HELLP/sangue , Pré-Eclâmpsia/sangue , Proteinúria/sangue , Adulto , Estudos de Casos e Controles , Feminino , Idade Gestacional , Humanos , Placenta/metabolismo , Contagem de Plaquetas , Gravidez
2.
J Am Heart Assoc ; 5(5)2016 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-27207969

RESUMO

BACKGROUND: Sphingosine-1-phosphate plays vital roles in cardiomyocyte physiology, myocardial ischemia-reperfusion injury, and ischemic preconditioning. The function of the cardiomyocyte sphingosine-1-phosphate receptor 1 (S1P1) in vivo is unknown. METHODS AND RESULTS: Cardiomyocyte-restricted deletion of S1P1 in mice (S1P1 (α) (MHCC) (re)) resulted in progressive cardiomyopathy, compromised response to dobutamine, and premature death. Isolated cardiomyocytes from S1P1 (α) (MHCC) (re) mice revealed reduced diastolic and systolic Ca(2+) concentrations that were secondary to reduced intracellular Na(+) and caused by suppressed activity of the sarcolemmal Na(+)/H(+) exchanger NHE-1 in the absence of S1P1. This scenario was successfully reproduced in wild-type cardiomyocytes by pharmacological inhibition of S1P1 or sphingosine kinases. Furthermore, Sarcomere shortening of S1P1 (α) (MHCC) (re) cardiomyocytes was intact, but sarcomere relaxation was attenuated and Ca(2+) sensitivity increased, respectively. This went along with reduced phosphorylation of regulatory myofilament proteins such as myosin light chain 2, myosin-binding protein C, and troponin I. In addition, S1P1 mediated the inhibitory effect of exogenous sphingosine-1-phosphate on ß-adrenergic-induced cardiomyocyte contractility by inhibiting the adenylate cyclase. Furthermore, ischemic precondtioning was abolished in S1P1 (α) (MHCC) (re) mice and was accompanied by defective Akt activation during preconditioning. CONCLUSIONS: Tonic S1P1 signaling by endogenous sphingosine-1-phosphate contributes to intracellular Ca(2+) homeostasis by maintaining basal NHE-1 activity and controls simultaneously myofibril Ca(2+) sensitivity through its inhibitory effect on adenylate cyclase. Cardioprotection by ischemic precondtioning depends on intact S1P1 signaling. These key findings on S1P1 functions in cardiac physiology may offer novel therapeutic approaches to cardiac diseases.


Assuntos
Cálcio/metabolismo , Cardiomiopatias/genética , Precondicionamento Isquêmico Miocárdico , Traumatismo por Reperfusão Miocárdica/genética , Miócitos Cardíacos/metabolismo , Receptores de Lisoesfingolipídeo/genética , Trocadores de Sódio-Hidrogênio/metabolismo , Potenciais de Ação , Adenilil Ciclases/metabolismo , Animais , Western Blotting , Miosinas Cardíacas/metabolismo , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/metabolismo , Proteínas de Transporte/metabolismo , Ecocardiografia , Imageamento por Ressonância Magnética , Camundongos , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Cadeias Leves de Miosina/metabolismo , Fosforilação , Tomografia por Emissão de Pósitrons , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Sarcômeros/metabolismo , Receptores de Esfingosina-1-Fosfato , Troponina I/metabolismo
3.
PLoS One ; 9(9): e107998, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25251068

RESUMO

OBJECTIVES: Spontaneously hypertensive rats (SHR) have been used frequently as a model for human essential hypertension. However, both the SHR and its normotensive control, the Wistar Kyoto rat (WKY), consist of genetically different sublines. We tested the hypothesis that the pathophysiology of vascular remodeling in hypertension differs among rat sublines. METHODS AND RESULTS: We studied mesenteric resistance arteries of WKY and SHR from three different sources, at 6 weeks and 5 months of age. Sublines of WKY and SHR showed differences in blood pressure, body weight, vascular remodeling, endothelial function, and vessel ultrastructure. Common features in small mesenteric arteries from SHR were an increase in wall thickness, wall-to-lumen ratio, and internal elastic lamina thickness. CONCLUSIONS: Endothelial dysfunction, vascular stiffening, and inward remodeling of small mesenteric arteries are not common features of hypertension, but are subline-dependent. Differences in genetic background associate with different types of vascular remodeling in hypertensive rats.


Assuntos
Artérias Mesentéricas/fisiologia , Ratos Endogâmicos SHR/fisiologia , Remodelação Vascular , Resistência Vascular , Animais , Pressão Sanguínea , Peso Corporal , Masculino , Artérias Mesentéricas/ultraestrutura , Ratos Endogâmicos WKY
4.
PLoS One ; 9(3): e91346, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24632890

RESUMO

Sphingosine-1-phosphate (S1P) is an agonist for five distinct G-protein coupled receptors, that is released by platelets, mast cells, erythrocytes and endothelial cells. S1P promotes endothelial cell barrier function and induces release of endothelial cell-specific storage-organelles designated Weibel-Palade bodies (WPBs). S1P-mediated enhancement of endothelial cell barrier function is dependent on S1P receptor 1 (S1PR1) mediated signaling events that result in the activation of the small GTPase Rac1. Recently, we have reported that Rac1 regulates epinephrine-induced WPB exocytosis following its activation by phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 1 (PREX1). S1P has also been described to induce WPB exocytosis. Here, we confirm that S1P induces release of WPBs using von Willebrand factor (VWF) as a marker. Using siRNA mediated knockdown of gene expression we show that S1PR1 is not involved in S1P-mediated release of WPBs. In contrast depletion of the S1PR3 greatly reduced S1P-induced release of VWF. S1P-mediated enhancement of endothelial barrier function was not affected by S1PR3-depletion whereas it was greatly impaired in cells lacking S1PR1. The Rho kinase inhibitor Y27632 completely abrogated S1P-mediated release of VWF. Also, the calcium chelator BAPTA-AM significantly reduced S1P-induced release of VWF. Our findings indicate that S1P-induced release of haemostatic, inflammatory and angiogenic components stored within WPBs depends on the S1PR3.


Assuntos
Células Endoteliais/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Corpos de Weibel-Palade/metabolismo , Amidas/farmacologia , Linhagem Celular , Regulação para Baixo , Células Endoteliais/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Expressão Gênica , Humanos , Ligação Proteica , Piridinas/farmacologia , Receptores de Lisoesfingolipídeo/genética , Receptores de Esfingosina-1-Fosfato
5.
J Hypertens ; 32(5): 1050-8; discussion 1058, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24569415

RESUMO

OBJECTIVE: Long-chain n-3 polyunsaturated fatty acids from oily fish reduce blood pressure (BP) in hypertension. Previously, we demonstrated that hypertension is associated with marked alterations in sphingolipid biology and elevated ceramide-induced vasoconstriction. Here we investigated in spontaneously hypertensive rats (SHRs) whether fish oil improves endothelial function including reduced vascular contraction induced via the sphingolipid cascade, resulting in reduced BP. METHODS: Twelve-week-old SHRs were fed a control or fish oil-enriched diet during 12 weeks, and BP was recorded. Plasma sphingolipid levels were quantified by mass spectrometry and the response of isolated carotid arteries towards different stimuli was measured. Furthermore, erythrocyte membrane fatty acid composition, thromboxane A2 formation and cytokine secretion in ex-vivo lipopolysaccharide-stimulated thoracic aorta segments were determined. RESULTS: The fish oil diet reduced the mean arterial BP (P < 0.001) and improved endothelial function, as indicated by a substantially increased relaxation potential towards ex-vivo methacholine exposure of the carotid arteries (P < 0.001). The long-chain n-3 polyunsaturated fatty acid diet resulted in altered levels of specific (glucosyl)ceramide subspecies (P < 0.05), reduced membrane arachidonic acid content (P < 0.001) and decreased thromboxane concentrations in plasma (P < 0.01). Concomitantly, the fish oil diet largely reduced ceramide-induced contractions (P < 0.01), which are predominantly mediated by thromboxane. Furthermore, thromboxane A2 and interleukin-10 were reduced in supernatants of lipopolysaccharide-stimulated thoracic aorta of SHRs fed the fish oil diet while RANTES (regulated on activation, normal T-cell expressed and secreted) was enhanced. This may contribute to reduced vasoconstriction in vivo. CONCLUSIONS: Dietary fish oil lowers BP in SHRs and improves endothelial function in association with suppression of sphingolipid-dependent vascular contraction.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Gorduras Insaturadas na Dieta/farmacologia , Endotélio Vascular/efeitos dos fármacos , Óleos de Peixe/farmacologia , Esfingolipídeos/fisiologia , Animais , Cromatografia Líquida , Espectrometria de Massas , Contração Muscular/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Esfingomielina Fosfodiesterase/metabolismo , Tromboxano B2/sangue
6.
Br J Pharmacol ; 166(4): 1411-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22251137

RESUMO

BACKGROUND AND PURPOSE: FTY720 (Fingolimod) is a recently approved orally administered drug for the treatment of multiple sclerosis. Phase II and III clinical trials have demonstrated that this drug modestly increases BP. We previously showed that inhibition of sphingosine kinase increases vascular tone and BP in hypertensive, but not normotensive rats. Since FTY720 is reported to have inhibitory effects on sphingosine kinase, we investigated whether FTY720 increases vascular tone and BP only in hypertensive rats via this mechanism. EXPERIMENTAL APPROACH: The contractile and BP modulating effects of FTY720 were studied in vivo and ex vivo (wire myography) in age-matched normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). KEY RESULTS: Oral administration of FTY720 induced an increase in mean arterial pressure in SHR, whereas a decrease in BP was observed in WKY rats, as measured 24 h after administration. Similar to the sphingosine kinase inhibitor dimethylsphingosine (DMS), FTY720 induced large contractions in isolated carotid arteries from SHR, but not in those from WKY. In contrast, the phosphorylated form of FTY720 did not induce contractions in isolated carotid arteries from SHR. FTY720-induced contractions were inhibited by endothelium denudation, COX and thromboxane synthase inhibitors, and by thromboxane receptor antagonism, indicating that (like DMS-induced contractions) they were endothelium-dependent and mediated by thromboxane A2. CONCLUSIONS AND IMPLICATIONS: These data demonstrate that FTY720 increases vascular tone and BP only in hypertensive rats, most likely as a result of its inhibitory effect on sphingosine kinase.


Assuntos
Artérias Carótidas/metabolismo , Endotélio Vascular/metabolismo , Hipertensão/metabolismo , Músculo Liso Vascular/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Resistência Vascular , Animais , Pressão Sanguínea/efeitos dos fármacos , Artérias Carótidas/citologia , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Inibidores de Ciclo-Oxigenase/farmacologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cloridrato de Fingolimode , Hipertensão/induzido quimicamente , Hipertensão/patologia , Hipertensão/fisiopatologia , Imunossupressores/efeitos adversos , Imunossupressores/química , Imunossupressores/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Fosforilação , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Propilenoglicóis/efeitos adversos , Propilenoglicóis/química , Propilenoglicóis/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Esfingosina/efeitos adversos , Esfingosina/análogos & derivados , Esfingosina/química , Esfingosina/farmacologia , Tromboxano A2/antagonistas & inibidores , Tromboxano A2/metabolismo , Resistência Vascular/efeitos dos fármacos , Vasoconstritores/efeitos adversos , Vasoconstritores/química , Vasoconstritores/farmacologia
7.
PLoS One ; 6(12): e29222, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22195025

RESUMO

BACKGROUND: We have previously shown that essential hypertension in humans and spontaneously hypertensive rats (SHR), is associated with increased levels of ceramide and marked alterations in sphingolipid biology. Pharmacological elevation of ceramide in isolated carotid arteries of SHR leads to vasoconstriction via a calcium-independent phospholipase A(2), cyclooxygenase-1 and thromboxane synthase-dependent release of thromboxane A(2). This phenomenon is almost absent in vessels from normotensive Wistar Kyoto (WKY) rats. Here we investigated whether lowering of blood pressure can reverse elevated ceramide levels and reduce ceramide-mediated contractions in SHR. METHODS AND FINDINGS: For this purpose SHR were treated for 4 weeks with the angiotensin II type 1 receptor antagonist losartan or the vasodilator hydralazine. Both drugs decreased blood pressure equally (SBP untreated SHR: 191±7 mmHg, losartan: 125±5 mmHg and hydralazine: 113±14 mmHg). The blood pressure lowering was associated with a 20-25% reduction in vascular ceramide levels and improved endothelial function of isolated carotid arteries in both groups. Interestingly, losartan, but not hydralazine treatment, markedly reduced sphingomyelinase-induced contractions. While both drugs lowered cyclooxygenase-1 expression, only losartan and not hydralazine, reduced the endothelial expression of calcium-independent phospholipase A(2). The latter finding may explain the effect of losartan treatment on sphingomyelinase-induced vascular contraction. CONCLUSION: In summary, this study corroborates the importance of sphingolipid biology in blood pressure control and specifically shows that blood pressure lowering reduces vascular ceramide levels in SHR and that losartan treatment, but not blood pressure lowering per se, reduces ceramide-mediated arterial contractions.


Assuntos
Anti-Hipertensivos/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Hidralazina/farmacologia , Losartan/farmacologia , Esfingolipídeos/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Vasos Sanguíneos/fisiopatologia , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Artérias Carótidas/fisiopatologia , Ceramidas/sangue , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Endotélio Vascular/fisiopatologia , Fosfolipases A2 do Grupo VI/metabolismo , Técnicas In Vitro , Masculino , Ratos , Ratos Endogâmicos SHR , Esfingomielina Fosfodiesterase/metabolismo , Vasoconstrição/efeitos dos fármacos
8.
PLoS One ; 6(7): e21817, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21818267

RESUMO

BACKGROUND: Hypertension is, amongst others, characterized by endothelial dysfunction and vascular remodeling. As sphingolipids have been implicated in both the regulation of vascular contractility and growth, we investigated whether sphingolipid biology is altered in hypertension and whether this is reflected in altered vascular function. METHODS AND FINDINGS: In isolated carotid arteries from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, shifting the ceramide/S1P ratio towards ceramide dominance by administration of a sphingosine kinase inhibitor (dimethylsphingosine) or exogenous application of sphingomyelinase, induced marked endothelium-dependent contractions in SHR vessels (DMS: 1.4±0.4 and SMase: 2.1±0.1 mN/mm; n = 10), that were virtually absent in WKY vessels (DMS: 0.0±0.0 and SMase: 0.6±0.1 mN/mm; n = 9, p<0.05). Imaging mass spectrometry and immunohistochemistry indicated that these contractions were most likely mediated by ceramide and dependent on iPLA(2), cyclooxygenase-1 and thromboxane synthase. Expression levels of these enzymes were higher in SHR vessels. In concurrence, infusion of dimethylsphingosine caused a marked rise in blood pressure in anesthetized SHR (42±4%; n = 7), but not in WKY (-12±10%; n = 6). Lipidomics analysis by mass spectrometry, revealed elevated levels of ceramide in arterial tissue of SHR compared to WKY (691±42 vs. 419±27 pmol, n = 3-5 respectively, p<0.05). These pronounced alterations in SHR sphingolipid biology are also reflected in increased plasma ceramide levels (513±19 pmol WKY vs. 645±25 pmol SHR, n = 6-12, p<0.05). Interestingly, we observed similar increases in ceramide levels (correlating with hypertension grade) in plasma from humans with essential hypertension (185±8 pmol vs. 252±23 pmol; n = 18 normotensive vs. n = 19 hypertensive patients, p<0.05). CONCLUSIONS: Hypertension is associated with marked alterations in vascular sphingolipid biology such as elevated ceramide levels and signaling, that contribute to increased vascular tone.


Assuntos
Ceramidas/metabolismo , Hipertensão/metabolismo , Adulto , Anestesia , Animais , Ácido Araquidônico/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiopatologia , Ceramidas/sangue , Cromatografia Líquida , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Ciclo-Oxigenase 1/metabolismo , Feminino , Humanos , Hipertensão/sangue , Hipertensão/fisiopatologia , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Fosfolipases A2 Independentes de Cálcio/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Esfingomielina Fosfodiesterase/farmacologia , Esfingosina/administração & dosagem , Esfingosina/farmacologia , Tromboxano A2/biossíntese , Vasoconstrição/efeitos dos fármacos
9.
Mol Cells ; 29(2): 105-11, 2010 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-20127284

RESUMO

Vasomotor tone is regulated by a complex interplay of a variety of extrinsic neurohumoral and intrinsic factors. It is the endothelium that has a major influence on smooth muscle cell tone via the release of intrinsic vasoactive factors and is therefore an important regulator of vasomotor tone. Sphingolipids are an emerging class of lipid mediators with important physiological properties. In the last two decades it has not only become increasingly clear that sphingolipid signaling plays a pivotal role in immune function, but also its role in the vascular system is now becoming more recognized. In this mini-review we will highlight the possible cross-talk between sphingolipids and intrinsic vasoactive factors released by the endothelium. Via this cross-talk sphingolipids can orchestrate vasomotor tone and may therefore also be involved in the pathophysiology of disease states associated with endothelial dysfunction.


Assuntos
Fatores Biológicos/metabolismo , Endotélio Vascular/fisiologia , Esfingolipídeos/metabolismo , Sistema Vasomotor/metabolismo , Animais , Humanos , Modelos Biológicos
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