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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Public Library of Science (PLoS)
2011-01-01
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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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