scholarly journals Soluble epoxide hydrolase gene deletion improves blood flow and reduces infarct size after cerebral ischemia in reproductively senescent female mice

2015 ◽  
Vol 5 ◽  
Author(s):  
Kristen L. Zuloaga ◽  
Wenri Zhang ◽  
Natalie E. Roese ◽  
Nabil J. Alkayed
Keyword(s):  
Blood Flow ◽  
Cerebral Ischemia ◽  
Infarct Size ◽  
Epoxide Hydrolase ◽  
Gene Deletion ◽  
Soluble Epoxide Hydrolase ◽  
Female Mice

scholarly journals Role of Soluble Epoxide Hydrolase in the Sex-Specific Vascular Response to Cerebral Ischemia

2009 ◽  
Vol 29 (8) ◽  
pp. 1475-1481 ◽  
Author(s):  
Wenri Zhang ◽  
Jeffrey J Iliff ◽  
Caitlyn J Campbell ◽  
Ruikang K Wang ◽  
Patricia D Hurn ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Ischemia ◽  
Infarct Size ◽  
Epoxide Hydrolase ◽  
Focal Cerebral Ischemia ◽  
Soluble Epoxide Hydrolase ◽  
Artery Occlusion ◽  
Male Mice ◽  
Key Enzyme

Soluble epoxide hydrolase (sEH), a key enzyme in the metabolism of vasodilator eicosanoids called epoxyeicosatrienoic acids (EETs), is sexually dimorphic and suppressed by estrogen. We determined if the sex difference in blood flow during focal cerebral ischemia is linked to sEH. Soluble epoxide hydrolase expression in brain, hydrolase activity in cerebral vessels, and plasma 14,15-dihydroxyeicosatrienoic acid (14,15-DHET) were determined in male and female wild-type (WT) and sEH knockout (sEHKO) mice. Male, female, and ovariectomized female WT and sEHKO mice were subjected to 2-h middle cerebral artery occlusion (MCAO) and infarct size was measured at 24 h of reperfusion. Laser—Doppler cortical perfusion during MCAO was compared among groups and differences in cortical blood flow rates were confirmed using in vivo quantitative optical microangiography. Cerebrovascular expression and activity of sEH and plasma 14,15-DHET were lower in WT female than male mice, and blood flow during MCAO was higher and infarct size was smaller in WT female compared with male mice. Sex differences in cerebral blood flow and ischemic damage were abolished after ovariectomy and were absent in sEHKO mice. We conclude that sEH is an important mechanism underlying sex-linked differences in blood flow and brain damage after cerebral ischemia.

scholarly journals Soluble Epoxide Hydrolase Gene Deletion Is Protective Against Experimental Cerebral Ischemia

Stroke ◽  
2008 ◽  
Vol 39 (7) ◽  
pp. 2073-2078 ◽  
Author(s):  
Wenri Zhang ◽  
Takashi Otsuka ◽  
Nobuo Sugo ◽  
Ardi Ardeshiri ◽  
Yazan K. Alhadid ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Epoxide Hydrolase ◽  
Gene Deletion ◽  
Soluble Epoxide Hydrolase ◽  
Experimental Cerebral Ischemia

scholarly journals The Angiotensin II Type 1—Receptor Blocker Candesartan Increases Cerebral Blood Flow, Reduces Infarct Size, and Improves Neurologic Outcome after Transient Cerebral Ischemia in Rats

2004 ◽  
Vol 24 (4) ◽  
pp. 467-474 ◽  
Author(s):  
Tobias Engelhorn ◽  
Sophia Goerike ◽  
Arnd Doerfler ◽  
Christine Okorn ◽  
Michael Forsting ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Angiotensin Ii ◽  
Cerebral Ischemia ◽  
Infarct Size ◽  
Laser Doppler Flowmetry ◽  
Transient Cerebral Ischemia ◽  
Doppler Flowmetry ◽  
Treatment Regimens

The goal of the present study was to test the impact of administration time of the angiotensin II type 1–receptor blocker candesartan on cerebral blood flow (CBF), infarct size, and neuroscore in transient cerebral ischemia. Therefore, 1-hour middle cerebral artery occlusion (MCAO) was followed by reperfusion. Rats received 0.5-mg/kg candesartan intravenously 2 hours before MCAO (pretreatment), 24 hours after MCAO, every 24 hours after MCAO, or 2 hours before and every 24 hours after MCAO. Infarct size (mm3) and a neuroscore at day 7 were compared with controls. CBF was quantified by radiolabeled microspheres and laser-Doppler flowmetry. Compared with controls (95 ± 8), infarct size in candesartan-treated groups was smaller (59 ± 5, 68 ± 10, 28 ± 3, and 15 ± 3, respectively; P < 0.05). Although there was no difference in neuroscore between pretreatment and controls (1.55 ± 0.18, 1.80 ± 0.13), other treatment regimens resulted in improved neuroscores (1.33 ± 0.16, 1.11 ± 0.11, 0.73 ± 0.15; P < 0.05). CBF in pretreated animals at 0.5 hours after MCAO was significantly higher than in controls (0.58 ± 0.09 mL · g−1 ·· min−1 and 44% ± 7% of baseline compared with 0.49 ± 0.06 mL · g−1 ·· min−1 and 37% ± 6%, microspheres and laser-Doppler flowmetry; P < 0.05). Thus, candesartan reduces infarct size even if administered only during reperfusion. Apart from pretreatment, other treatment regimens result in significantly improved neuroscores. In the acute phase of cerebral ischemia, candesartan increases CBF.

scholarly journals Soluble epoxide hydrolase gene deletion reduces survival after cardiac arrest and cardiopulmonary resuscitation

Resuscitation ◽  
2008 ◽  
Vol 76 (1) ◽  
pp. 89-94 ◽  
Author(s):  
Michael P. Hutchens ◽  
Takaaki Nakano ◽  
Jennifer Dunlap ◽  
Richard J. Traystman ◽  
Patricia D. Hurn ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Cardiopulmonary Resuscitation ◽  
Epoxide Hydrolase ◽  
Gene Deletion ◽  
Soluble Epoxide Hydrolase

scholarly journals Soluble Epoxide Hydrolase Deletion Limits High-Fat Diet-Induced Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Karen M. Wagner ◽  
Jun Yang ◽  
Christophe Morisseau ◽  
Bruce D. Hammock
Keyword(s):  
Fatty Acids ◽  
High Fat Diet ◽  
Epoxide Hydrolase ◽  
Biological Effects ◽  
Soluble Epoxide Hydrolase ◽  
Bioactive Lipids ◽  
High Fat ◽  
Female Mice ◽  
Epoxy Fatty Acids ◽  
Fat Diets

The soluble epoxide hydrolase (sEH) enzyme is a major regulator of bioactive lipids. The enzyme is highly expressed in liver and kidney and modulates levels of endogenous epoxy-fatty acids, which have pleiotropic biological effects including limiting inflammation, neuroinflammation, and hypertension. It has been hypothesized that inhibiting sEH has beneficial effects on limiting obesity and metabolic disease as well. There is a body of literature published on these effects, but typically only male subjects have been included. Here, we investigate the role of sEH in both male and female mice and use a global sEH knockout mouse model to compare the effects of diet and diet-induced obesity. The results demonstrate that sEH activity in the liver is modulated by high-fat diets more in male than in female mice. In addition, we characterized the sEH activity in high fat content tissues and demonstrated the influence of diet on levels of bioactive epoxy-fatty acids. The sEH KO animals had generally increased epoxy-fatty acids compared to wild-type mice but gained less body weight on higher-fat diets. Generally, proinflammatory prostaglandins and triglycerides were also lower in livers of sEH KO mice fed HFD. Thus, sEH activity, prostaglandins, and triglycerides increase in male mice on high-fat diet but are all limited by sEH ablation. Additionally, these changes also occur in female mice though at a different magnitude and are also improved by knockout of the sEH enzyme.

Soluble epoxide hydrolase gene deletion reduces inflammation after stroke

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S93-S93
Author(s):  
Ines P Koerner ◽  
Wenri Zhang ◽  
Patricia D Hurn ◽  
Dennis Koop ◽  
Nabil J Alkayed
Keyword(s):  
Epoxide Hydrolase ◽  
Gene Deletion ◽  
Soluble Epoxide Hydrolase

GSK2256294 Decreases sEH (Soluble Epoxide Hydrolase) Activity in Plasma, Muscle, and Adipose and Reduces F2-Isoprostanes but Does Not Alter Insulin Sensitivity in Humans

Hypertension ◽  
2021 ◽  
Author(s):  
James M. Luther ◽  
Justina Ray ◽  
Dawei Wei ◽  
John R. Koethe ◽  
Latoya Hannah ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Epoxide Hydrolase ◽  
Renal Plasma Flow ◽  
Soluble Epoxide Hydrolase ◽  
Improve Insulin Sensitivity ◽  
Double Blind ◽  
Phosphorylated Akt

Epoxyeicosatrienoic acids (EETs) reduce blood pressure by acting in the vasculature and kidney, and interventions to increase circulating EETs improve insulin sensitivity and prevent diabetes in animal models. Inhibition of EET hydrolysis with a sEH (soluble epoxide hydrolase) inhibitor is an attractive approach for hypertension and diabetes. We tested the hypothesis that sEH inhibition increases circulating EETs, reduces blood pressure, and improves insulin sensitivity, blood flow, and inflammation in a randomized, double-blind, placebo-controlled crossover study. Sixteen participants with obesity and prediabetes were randomized to GSK2256294 10 mg QD or placebo for 7 days, insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and adipose and muscle tissues biopsies were performed to assess insulin-stimulated Akt phosphorylation. We assessed tissue and plasma EETs and their respective diol concentrations and sEH activity within plasma, muscle, and adipose tissues. GSK2256294 reduced circulating and adipose tissue sEH activity, but blood pressure, circulating EET, and tissue EETs were unchanged. Plasma sEH activity correlated with muscle and adipose tissue sEH activity. Insulin sensitivity assessed during hyperinsulinemic clamps, as well as adipose and muscle phosphorylated-Akt/Akt expression were similar during GSK2256294 and placebo. sEH inhibition with GSK2256294 reduced plasma F2-isoprostanes (50.7±15.8 versus 37.2±17.3 pg/mL; P =0.03) but not IL (interleukin)-6. Resting blood pressure, forearm blood flow, and renal plasma flow were similar during GSK2256294 and placebo. We demonstrate that GSK2256294 administration for 7 days effectively inhibits sEH activity in plasma, muscle, and adipose tissue and reduces F2-isoprostanes—a marker of oxidative stress—but does not improve insulin sensitivity or blood pressure.

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