title: Dietary fish oil improves endothelial function and lowers blood pressure via suppression of sphingolipid-mediated contractions in spontaneously hypertensive rats.
abstract: 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.
authors.affiliation: aDivision of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht bDivision of Pharmacology & Pharmacotherapy, Academic Medical Center, Amsterdam cNutricia Research, Centre for Specialised Nutrition, Utrecht, The Netherlands dHunter Holmes McGuire Veterans Administration Medical Center eDepartment of Biochemistry & Molecular Biology, Virginia Commonwealth University fVirginia Commonwealth University Reanimation Engineering Science Center (VCURES) gThe Massey Cancer Center, Richmond, Virginia, USA.
authors.forename: Lieke W J
authors.initials: LW
authors.lastname: van den Elsen
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: Aggie M H
authors.initials: AM
authors.lastname: van Winssen
authors.forename: Martin
authors.initials: M
authors.lastname: Balvers
authors.forename: Dayanjan S
authors.initials: DS
authors.lastname: Wijesinghe
authors.forename: Charles E
authors.initials: CE
authors.lastname: Chalfant
authors.forename: Johan
authors.initials: J
authors.lastname: Garssen
authors.forename: Linette E M
authors.initials: LE
authors.lastname: Willemsen
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Alewijnse
authors.forename: Stephan L M
authors.initials: SL
authors.lastname: Peters
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002853:Chromatography, Liquid; D004042:Dietary Fats, Unsaturated / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D005395:Fish Oils / Q000494:pharmacology*; D013058:Mass Spectrometry; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D013107:Sphingolipids / Q000502:physiology*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013929:Thromboxane B2 / Q000097:blood
chemical_list: D004042:Dietary Fats, Unsaturated; D005395:Fish Oils; D013107:Sphingolipids; D013929:Thromboxane B2; D013108:Sphingomyelin Phosphodiesterase