title: Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Léon J A
authors.initials: LJ
authors.lastname: Spijkers
authors.forename: Rob F P
authors.initials: RF
authors.lastname: van den Akker
authors.forename: Ben J A
authors.initials: BJ
authors.lastname: Janssen
authors.forename: Jacques J
authors.initials: JJ
authors.lastname: Debets
authors.forename: Jo G R
authors.initials: JG
authors.lastname: De Mey
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
authors.forename: Bert-Jan H
authors.initials: BJ
authors.lastname: van den Born
authors.forename: Dayanjan S
authors.initials: DS
authors.lastname: Wijesinghe
authors.forename: Charles E
authors.initials: CE
authors.lastname: Chalfant
authors.forename: Luke
authors.initials: L
authors.lastname: MacAleese
authors.forename: Gert B
authors.initials: GB
authors.lastname: Eijkel
authors.forename: Ron M A
authors.initials: RM
authors.lastname: Heeren
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Alewijnse
authors.forename: Stephan L M
authors.initials: SL
authors.lastname: Peters
mesh_terms: D000328:Adult; D000758:Anesthesia; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000503:physiopathology; D002518:Ceramides / Q000097:blood / Q000378:metabolism*; D002853:Chromatography, Liquid; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D054512:Phospholipases A2, Calcium-Independent / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013108:Sphingomyelin Phosphodiesterase / Q000494:pharmacology; D013110:Sphingosine / Q000008:administration & dosage / Q000494:pharmacology; D013928:Thromboxane A2 / Q000096:biosynthesis; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D002518:Ceramides; D016718:Arachidonic Acid; D013928:Thromboxane A2; D051545:Cyclooxygenase 1; D054512:Phospholipases A2, Calcium-Independent; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine