Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide.

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...

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Main Authors: Léon J A Spijkers, Rob F P van den Akker, Ben J A Janssen, Jacques J Debets, Jo G R De Mey, Erik S G Stroes, Bert-Jan H van den Born, Dayanjan S Wijesinghe, Charles E Chalfant, Luke MacAleese, Gert B Eijkel, Ron M A Heeren, Astrid E Alewijnse, Stephan L M Peters
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2011-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3139577?pdf=render
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author Léon J A Spijkers
Rob F P van den Akker
Ben J A Janssen
Jacques J Debets
Jo G R De Mey
Erik S G Stroes
Bert-Jan H van den Born
Dayanjan S Wijesinghe
Charles E Chalfant
Luke MacAleese
Gert B Eijkel
Ron M A Heeren
Astrid E Alewijnse
Stephan L M Peters
author_facet Léon J A Spijkers
Rob F P van den Akker
Ben J A Janssen
Jacques J Debets
Jo G R De Mey
Erik S G Stroes
Bert-Jan H van den Born
Dayanjan S Wijesinghe
Charles E Chalfant
Luke MacAleese
Gert B Eijkel
Ron M A Heeren
Astrid E Alewijnse
Stephan L M Peters
author_sort Léon J A Spijkers
collection DOAJ
description 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.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).Hypertension is associated with marked alterations in vascular sphingolipid biology such as elevated ceramide levels and signaling, that contribute to increased vascular tone.
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spelling doaj.art-7ea95473f792457ab3148a3baa0d7cd52022-12-21T19:52:51ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0167e2181710.1371/journal.pone.0021817Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide.Léon J A SpijkersRob F P van den AkkerBen J A JanssenJacques J DebetsJo G R De MeyErik S G StroesBert-Jan H van den BornDayanjan S WijesingheCharles E ChalfantLuke MacAleeseGert B EijkelRon M A HeerenAstrid E AlewijnseStephan L M PetersHypertension 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.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).Hypertension is associated with marked alterations in vascular sphingolipid biology such as elevated ceramide levels and signaling, that contribute to increased vascular tone.http://europepmc.org/articles/PMC3139577?pdf=render
spellingShingle Léon J A Spijkers
Rob F P van den Akker
Ben J A Janssen
Jacques J Debets
Jo G R De Mey
Erik S G Stroes
Bert-Jan H van den Born
Dayanjan S Wijesinghe
Charles E Chalfant
Luke MacAleese
Gert B Eijkel
Ron M A Heeren
Astrid E Alewijnse
Stephan L M Peters
Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide.
PLoS ONE
title Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide.
title_full Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide.
title_fullStr Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide.
title_full_unstemmed Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide.
title_short Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide.
title_sort hypertension is associated with marked alterations in sphingolipid biology a potential role for ceramide
url http://europepmc.org/articles/PMC3139577?pdf=render
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