scholarly journals The Soluble Epoxide Hydrolase Inhibitor AR9281 Decreases Blood Pressure, Ameliorates Renal Injury and Improves Vascular Function in Hypertension

2009 ◽  
Vol 2 (3) ◽  
pp. 217-227 ◽  
Author(s):  
John Imig ◽  
Margaret Carpenter ◽  
Sean Shaw
Keyword(s):  
Blood Pressure ◽  
Renal Injury ◽  
Vascular Function ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase Inhibitor

scholarly journals Inhibition of Soluble Epoxide Hydrolase Attenuates Bosutinib-Induced Blood Pressure Elevation

Hypertension ◽  
2021 ◽  
Author(s):  
Zhen Cui ◽  
Bochuan Li ◽  
Yanhong Zhang ◽  
Jinlong He ◽  
Xuelian Shi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Side Effects ◽  
Epoxide Hydrolase ◽  
Endothelial Activation ◽  
Soluble Epoxide Hydrolase ◽  
Mesenteric Arteries ◽  
Arterial Blood ◽  
Soluble Epoxide Hydrolase Inhibitor

Endothelial cells play a critical role in maintaining homeostasis of vascular function, and endothelial activation is involved in the initial step of atherogenesis. Previously, we reported that Abl kinase mediates shear stress–induced endothelial activation. Bosutinib, a dual inhibitor of Src and Abl kinases, exerts an atheroprotective effect; however, recent studies have demonstrated an increase in the incidence of side effects associated with bosutinib, including increased arterial blood pressure (BP). To understand the effects of bosutinib on BP regulation and the mechanistic basis for novel treatment strategies against vascular dysfunction, we generated a line of mice conditionally lacking c-Abl in endothelial cells (endothelial cell- Abl KO ). Knockout mice and their wild-type littermates ( Abl f/f ) were orally administered a clinical dose of bosutinib, and their BP was monitored. Bosutinib treatment increased BP in both endothelial cell- Abl KO and Abl f/f mice. Furthermore, acetylcholine-evoked endothelium-dependent relaxation of the mesenteric arteries was impaired by bosutinib treatment. RNA sequencing of mesenteric arteries revealed that the CYP (cytochrome P450)-dependent metabolic pathway was involved in regulating BP after bosutinib treatment. Additionally, bosutinib treatment led to an upregulation of soluble epoxide hydrolase in the arteries and a lower plasma content of eicosanoid metabolites in the CYP pathway in mice. Treatment with 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea, a soluble epoxide hydrolase inhibitor, reversed the bosutinib-induced changes to the eicosanoid metabolite profile, endothelium-dependent vasorelaxation, and BP. Thus, the present study demonstrates that upregulation of soluble epoxide hydrolase mediates bosutinib-induced elevation of BP, independent of c-Abl. The addition of soluble epoxide hydrolase inhibitor in patients treated with bosutinib may aid in preventing vascular side effects.

Abstract 309: Role of Hemeoxygenase in the Reno-Protective Effects of Soluble Epoxide Hydrolase Inhibition In Diabetic Spontaneously Hypertensive Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Ahmed A Elmarakby ◽  
Jessica Faulkner ◽  
Chelsey Pye ◽  
Babak Baban ◽  
Katelyn Rouch ◽  
...  
Keyword(s):  
Protective Effect ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Spontaneously Hypertensive Rats ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Control Group ◽  
Protective Effects ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive

We previously showed that inhibition of soluble epoxide hydrolase (sEH) increased epoxyeicosatrienoic acids (EETs) levels and reduced renal injury in diabetic mice and these changes were associated with induction of hemeoxygenase-1 (HO-1). The present study determines whether the inhibition of HO negates the reno-protective effect of sEH inhibition in diabetic spontaneously hypertensive rats as a model of diabetic nephropathy in which hypertension coexists with diabetes. After six weeks of induction of diabetes with streptozotocin, SHR were divided into the following groups: untreated, treated with the sEH inhibitor, trans -4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (AUCB), treated with the HO inhibitor, stannous mesoporphyrin (SnMP), and treated with both inhibitors for four more weeks; non diabetic SHR served as a control group. Although inhibition of sEH increased renal EETs/DHETEs ratio and HO-1 activity in diabetic SHR, it did not significantly alter blood pressure (plasma EETs/DHETEs ratio was 0.5± 0.1 in AUCB-treated vs. 0.1± 0.01 in untreated diabetic SHR, P<0.05). Treatment of diabetic SHR with AUCB reduced the elevation in urinary albumin and nephrin excretion (albuminuria was 6.5± 0.5 in AUCB-treated diabetic SHR vs. 9± 1.7 mg/day in untreated diabetic SHR and nephrinuria was 70±11 in AUCB-treated diabetic SHR vs. 111± 9 μg/day in untreated diabetic SHR, P<0.05) whereas co-administration of SnMP with AUCB prevented these changes (albuminuria was 10.6± 0.6 mg/day and nephrinuria was 91±11 μg/day). Immunohistochemical analysis revealed elevations in renal fibrosis and apoptosis as evidenced by increased renal TGF-β, fibronectin and annexin V expression in diabetic SHR and these changes were reduced with sEH inhibition. Co-administration of SnMP with AUCB prevented its ability to reduce renal fibrosis and apoptosis in diabetic SHR. In addition, SnMP treatment also prevented AUCB-induced decreases in renal macrophage infiltration and renal TGF-β, NFκB and MCP-1 levels in diabetic SHR. These data suggest that HO-1 induction is involved in the protective effect of sEH inhibition against diabetic renal injury.

scholarly journals Soluble Epoxide Hydrolase Inhibitor Attenuates Lipopolysaccharide-Induced Acute Lung Injury and Improves Survival in Mice

Shock ◽  
2017 ◽  
Vol 47 (5) ◽  
pp. 638-645 ◽  
Author(s):  
Yong Zhou ◽  
Tian Liu ◽  
Jia-Xi Duan ◽  
Ping Li ◽  
Guo-Ying Sun ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase Inhibitor
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