Cytochrome P450 2J2 is protective against global cerebral ischemia in transgenic mice

Prostaglandins Other Lipid Mediat. 2012 Dec;99(3-4):68-78. doi: 10.1016/j.prostaglandins.2012.09.004. Epub 2012 Oct 2.

Abstract

Cytochrome P450 epoxygenase metabolites of arachidonic acid, EETs, have multiple cardiovascular effects, including reduction of blood pressure, protection against myocardial ischemia-reperfusion injury, and attenuation of endothelial apoptosis. This study investigated the hypothesis that transgenic mice with endothelial overexpression of CYP2J2 (Tie2-CYP2J2-Tr) would be protected against global cerebral ischemia induced by bilateral common carotid artery occlusion (BCCAO) and action mechanisms of EETs on cerebral ischemia in cultures of astrocytes exposed to oxygen-glucose deprivation (OGD). Tie2-CYP2J2-Tr mice had significantly increased CYP2J2 expression, increased 14,15-EET production, increases regional cerebral blood flow (rCBF) and microvascular density, decreased ROS production, decreased brain infarct size and apoptosis after ischemia compared to wild type mice, these were associated with increased activation of the PI3K/AKT and apoptosis-related protein in ischemic brain. Addition of exogenous EETs or CYP2J2 transfection attenuated OGD-induced apoptosis in astrocytes via activation of PI3K/AKT and anti-apoptosis pathways. However, these effects were reduced by pretreatments with inhibitor of the PI3K (LY294002) and 14,15-EET (14,15-EEZE), respectively. These results indicate that CYP2J2 overexpression exerts marked neuroprotective effects against ischemic injury by a mechanism linked to increased level of circulating EETs and increases CBF and reduction of apoptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8,11,14-Eicosatrienoic Acid / analogs & derivatives
  • 8,11,14-Eicosatrienoic Acid / metabolism
  • 8,11,14-Eicosatrienoic Acid / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Astrocytes / cytology
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Brain Ischemia / enzymology*
  • Brain Ischemia / genetics
  • Brain Ischemia / physiopathology
  • Cell Hypoxia
  • Cells, Cultured
  • Cerebral Infarction / enzymology*
  • Cerebral Infarction / genetics
  • Cerebral Infarction / physiopathology
  • Cerebrovascular Circulation
  • Coronary Occlusion / enzymology*
  • Coronary Occlusion / genetics
  • Coronary Occlusion / physiopathology
  • Cytochrome P-450 CYP2J2
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism
  • Gene Expression / drug effects
  • Glucose / deficiency
  • Male
  • Mice
  • Mice, Transgenic
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects

Substances

  • 14,15-eicosa-5-enoic acid
  • Apoptosis Regulatory Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • 14,15-epoxy-5,8,11-eicosatrienoic acid
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP2J2
  • Proto-Oncogene Proteins c-akt
  • 8,11,14-Eicosatrienoic Acid
  • Glucose