title: Protective role of p450 epoxyeicosanoids in subarachnoid hemorrhage.
abstract: BACKGROUND
  Patients recovering from aneurysmal subarachnoid hemorrhage (SAH) are at risk for developing delayed cerebral ischemia (DCI). Experimental and human studies implicate the vasoconstrictor P450 eicosanoid 20-hydroxyeicosatetraenoic acid (20-HETE) in the pathogenesis of DCI. To date, no studies have evaluated the role of vasodilator epoxyeicosatrienoic acids (EETs) in DCI.
  
  
  METHODS
  Using mass spectrometry, we measured P450 eicosanoids in cerebrospinal fluid (CSF) from 34 SAH patients from 1 to 14 days after admission. CSF eicosanoid levels were compared in patients who experienced DCI versus those who did not. We then studied the effect of EETs in a model of SAH using mice lacking the enzyme soluble epoxide hydrolase (sEH), which catabolizes EETs into their inactive diol. To assess changes in vessel morphology and cortical perfusion in the mouse brain, we used optical microangiography, a non-invasive coherence-based imaging technique.
  
  
  RESULTS
  Along with increases in 20-HETE, we found that CSF levels of 14,15-EET were elevated in SAH patients compared to control CSF, and levels were significantly higher in patients who experienced DCI compared to those who did not. Mice lacking sEH had elevated 14,15-EET and were protected from the delayed decrease in microvascular cortical perfusion after SAH, compared to wild type mice.
  
  
  CONCLUSIONS
  Our findings suggest that P450 eicosanoids play an important role in the pathogenesis of DCI. While 20-HETE may contribute to the development of DCI, 14,15-EET may afford protection against DCI. Strategies to enhance 14,15-EET, including sEH inhibition, should be considered as part of a comprehensive approach to prevent DCI.
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Dominic A
authors.initials: DA
authors.lastname: Siler
authors.forename: Ross P
authors.initials: RP
authors.lastname: Martini
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Ward
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Nelson
authors.forename: Rohan N
authors.initials: RN
authors.lastname: Borkar
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Zuloaga
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Liu
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Fairbanks
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Raskin
authors.forename: Valerie C
authors.initials: VC
authors.lastname: Anderson
authors.forename: Aclan
authors.initials: A
authors.lastname: Dogan
authors.forename: Ruikang K
authors.initials: RK
authors.lastname: Wang
authors.forename: Nabil J
authors.initials: NJ
authors.lastname: Alkayed
authors.forename: Justin S
authors.initials: JS
authors.lastname: Cetas
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid; D000368:Aged; D000818:Animals; D002545:Brain Ischemia / Q000134:cerebrospinal fluid*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000134:cerebrospinal fluid*; D008297:Male; D051379:Mice; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000134:cerebrospinal fluid*; D013345:Subarachnoid Hemorrhage / Q000134:cerebrospinal fluid*
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D018696:Neuroprotective Agents; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid