Protective Role of P450 Epoxyeicosanoids in Subarachnoid Hemorrhage

Dominic A. Siler, Ross P. Martini, Jonathan P. Ward, Jonathan W. Nelson, Rohan N. Borkar, Kristen L. Zuloaga, Jesse J. Liu, Stacy L. Fairbanks, Jeffrey S. Raskin, Valerie Anderson, Aclan Dogan, Ruikang K. Wang, Nabil Alkayed, Justin Cetas

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)306-319
Number of pages14
JournalNeurocritical Care
Volume22
Issue number2
DOIs
StatePublished - 2015

Fingerprint

Subarachnoid Hemorrhage
Brain Ischemia
Eicosanoids
Epoxide Hydrolases
Cerebrospinal Fluid
Perfusion
Vasoconstrictor Agents
Vasodilator Agents
Mass Spectrometry
Acids
14,15-epoxy-5,8,11-eicosatrienoic acid
Brain
Enzymes

Keywords

  • 20-HETE
  • Delayed cerebral ischemia
  • Epoxyeicosatrienoic acid
  • Soluble epoxide hydrolase
  • Subarachnoid hemorrhage

ASJC Scopus subject areas

  • Clinical Neurology
  • Critical Care and Intensive Care Medicine

Cite this

Siler, D. A., Martini, R. P., Ward, J. P., Nelson, J. W., Borkar, R. N., Zuloaga, K. L., ... Cetas, J. (2015). Protective Role of P450 Epoxyeicosanoids in Subarachnoid Hemorrhage. Neurocritical Care, 22(2), 306-319. https://doi.org/10.1007/s12028-014-0011-y

Protective Role of P450 Epoxyeicosanoids in Subarachnoid Hemorrhage. / Siler, Dominic A.; Martini, Ross P.; Ward, Jonathan P.; Nelson, Jonathan W.; Borkar, Rohan N.; Zuloaga, Kristen L.; Liu, Jesse J.; Fairbanks, Stacy L.; Raskin, Jeffrey S.; Anderson, Valerie; Dogan, Aclan; Wang, Ruikang K.; Alkayed, Nabil; Cetas, Justin.

In: Neurocritical Care, Vol. 22, No. 2, 2015, p. 306-319.

Research output: Contribution to journalArticle

Siler, DA, Martini, RP, Ward, JP, Nelson, JW, Borkar, RN, Zuloaga, KL, Liu, JJ, Fairbanks, SL, Raskin, JS, Anderson, V, Dogan, A, Wang, RK, Alkayed, N & Cetas, J 2015, 'Protective Role of P450 Epoxyeicosanoids in Subarachnoid Hemorrhage', Neurocritical Care, vol. 22, no. 2, pp. 306-319. https://doi.org/10.1007/s12028-014-0011-y
Siler DA, Martini RP, Ward JP, Nelson JW, Borkar RN, Zuloaga KL et al. Protective Role of P450 Epoxyeicosanoids in Subarachnoid Hemorrhage. Neurocritical Care. 2015;22(2):306-319. https://doi.org/10.1007/s12028-014-0011-y
Siler, Dominic A. ; Martini, Ross P. ; Ward, Jonathan P. ; Nelson, Jonathan W. ; Borkar, Rohan N. ; Zuloaga, Kristen L. ; Liu, Jesse J. ; Fairbanks, Stacy L. ; Raskin, Jeffrey S. ; Anderson, Valerie ; Dogan, Aclan ; Wang, Ruikang K. ; Alkayed, Nabil ; Cetas, Justin. / Protective Role of P450 Epoxyeicosanoids in Subarachnoid Hemorrhage. In: Neurocritical Care. 2015 ; Vol. 22, No. 2. pp. 306-319.
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AU - Siler, Dominic A.

AU - Martini, Ross P.

AU - Ward, Jonathan P.

AU - Nelson, Jonathan W.

AU - Borkar, Rohan N.

AU - Zuloaga, Kristen L.

AU - Liu, Jesse J.

AU - Fairbanks, Stacy L.

AU - Raskin, Jeffrey S.

AU - Anderson, Valerie

AU - Dogan, Aclan

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AU - Alkayed, Nabil

AU - Cetas, Justin

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KW - Soluble epoxide hydrolase

KW - Subarachnoid hemorrhage

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