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.

scholarly journals Soluble epoxide hydrolase gene deletion attenuates renal injury and inflammation with DOCA-salt hypertension

2009 ◽  
Vol 297 (3) ◽  
pp. F740-F748 ◽  
Author(s):  
Marlina Manhiani ◽  
Jeffrey E. Quigley ◽  
Sarah F. Knight ◽  
Shiva Tasoobshirazi ◽  
TarRhonda Moore ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Epoxide Hydrolase ◽  
Gene Deletion ◽  
Soluble Epoxide Hydrolase ◽  
Glomerular Injury ◽  
Renal Protection ◽  
Renal Inflammation ◽  
Arterial Blood ◽  
Salt Hypertension ◽  
Salt Sensitive Hypertension

Inhibition of soluble epoxide hydrolase (sEH) has been shown to be renal protective in rat models of salt-sensitive hypertension. Here, we hypothesize that targeted disruption of the sEH gene (Ephx2) prevents both renal inflammation and injury in deoxycorticosterone acetate plus high salt (DOCA-salt) hypertensive mice. Mean arterial blood pressure (MAP) increased significantly in the DOCA-salt groups, and MAP was lower in Ephx2−/− DOCA-salt (129 ± 3 mmHg) compared with wild-type (WT) DOCA-salt (145 ± 2 mmHg) mice. Following 21 days of treatment, WT DOCA-salt urinary MCP-1 excretion increased from control and was attenuated in the Ephx2−/− DOCA-salt group. Macrophage infiltration was reduced in Ephx2−/− DOCA-salt compared with WT DOCA-salt mice. Albuminuria increased in WT DOCA-salt (278 ± 55 μg/day) compared with control (17 ± 1 μg/day) and was blunted in the Ephx2−/− DOCA-salt mice (97 ± 23 μg/day). Glomerular nephrin expression demonstrated an inverse relationship with albuminuria. Nephrin immunofluorescence was greater in the Ephx2−/− DOCA-salt group (3.4 ± 0.3 RFU) compared with WT DOCA-salt group (1.1 ± 0.07 RFU). Reduction in renal inflammation and injury was also seen in WT DOCA-salt mice treated with a sEH inhibitor { trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid; tAUCB}, demonstrating that the C-terminal hydrolase domain of the sEH enzyme is responsible for renal protection with DOCA-salt hypertension. These data demonstrate that Ephx2 gene deletion decreases blood pressure, attenuates renal inflammation, and ameliorates glomerular injury in DOCA-salt hypertension.

scholarly journals Soluble Epoxide Hydrolase Inhibition Lowers Arterial Blood Pressure in Angiotensin II Hypertension

Hypertension ◽  
2002 ◽  
Vol 39 (2) ◽  
pp. 690-694 ◽  
Author(s):  
John D. Imig ◽  
Xueying Zhao ◽  
Jorge H. Capdevila ◽  
Christophe Morisseau ◽  
Bruce D. Hammock
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Arterial Blood Pressure ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Arterial Blood

scholarly journals Sortilin evokes endothelial dysfunction and arterial hypertension through the dysregulation of sphingolipid metabolism and oxidative stress

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P Di Pietro ◽  
M Oliveti ◽  
E Sommella ◽  
A Damato ◽  
A Puca ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Endothelial Cells ◽  
Nadph Oxidase ◽  
Endothelial Function ◽  
Acid Sphingomyelinase ◽  
Mesenteric Arteries ◽  
Hypertensive Patients ◽  
Arterial Blood ◽  
Sphingosine 1 Phosphate

Abstract Background Sortilin, a member of vacuolar protein sorting domain family Vps10, has been positively correlated with vascular and metabolic disorders in humans. Previous study has shown that, in response to Fas receptor stimulation, sortilin together with acid sphingomyelinase (ASMase) promote the clustering of lipid rafts and subsequent activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in coronary endothelial cells. However, whether sortilin plays a role in endothelial cells function is currently unknown. Purpose To assess whether sortilin per se was able to influence vascular function, thereby contributing to the pathogenesis of cardiovascular diseases. Methods Pressure myography was used to study vascular reactivity of mesenteric arteries. To investigate the involvement of acid sphingomyelinase (ASM), we performed gene silencing approach and fluorometric activity assay. NADPH oxidase lucigenin assay was used to evaluate oxidative stress in endothelial cells and resistance vessels. The effects of circulating sortilin on cardiovascular system was evaluated by systemic delivery of recombinant sortilin protein to wild-type (WT), sphingosine-1-phosphate receptor 3 (S1P3) and NADPH oxidase 2 (gp91phox/NOX2) deficient mice. Systolic arterial blood pressure (SBP) was noninvasively registered in conscious mice by tail-cuff blood monitoring. Finally, to explore the translational relevance of sortilin, we measured sortilin and NOX2 soluble derived peptide levels using ELISA and quantified sphingosine-1-phosphate (S1P) by liquid chromatography–tandem mass spectrometry (LC-MS/MS) in plasma of hypertensive patients. Results Here we demonstrated that sortilin evoked endothelial dysfunction in mesenteric arteries due to increased NADPH oxidase-derived oxidative stress. Knockdown of ASM successfully prevented impairment of endothelial function. Using the inhibitor of sphingosine kinase type 1 (SphK1), sortilin failed to evoke endothelial impairment as well as NADPH oxidase activation. In endothelial cells, sortilin induced S1P-dependent activation of Rac1/NOX2 signaling axis, which was prevented by TY-52156, an antagonist of lysosphingolipid receptor S1P3. In vivo sortilin administration induced arterial hypertension in WT mice. In contrast, genetic deletion of S1P3 and gp91phox/NOX2 resulted in preservation of endothelial function and SBP unchanged levels after 14 days of systemic sortilin administration. Finally, to translate these research findings into a clinical setting, we found that hypertensive patients have higher plasma levels of sortilin, ASMase, S1P and soluble NOX2 derived peptide than normotensive subjects. Conclusions These results demonstrate the pathologic role of sortilin in the modulation of endothelial function and arterial blood pressure, suggesting that sortilin and its mediators might represent novel therapeutic targets in vascular diseases and hypertension. Funding Acknowledgement Type of funding source: None

scholarly journals Modulation of Arachidonic Acid Metabolism in the Rat Kidney by Sulforaphane: Implications for Regulation of Blood Pressure

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Fawzy Elbarbry ◽  
Anke Vermehren-Schmaedick ◽  
Agnieszka Balkowiec
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Arachidonic Acid ◽  
Epoxide Hydrolase ◽  
Rat Kidney ◽  
Soluble Epoxide Hydrolase ◽  
Arachidonic Acid Metabolism ◽  
Dependent Manner ◽  
Shr Rats ◽  
Arterial Blood

Background. We investigated the effects of sulforaphane (SF), the main active isothiocyanate in cruciferous vegetables, on arachidonic acid (AA) metabolism in the kidney and its effect on arterial blood pressure, using spontaneously hypertensive rats (SHR) as models. Methods. Rats were treated for 8 weeks with either drinking water alone (control) or SF (20 or 40 mg/kg) added to drinking water. Mean arterial pressure (MAP) was measured at 7-day intervals throughout the study. At the end of treatment rats were euthanized, and kidneys were harvested to prepare microsomes and measure enzymes involved in regulation of vasoactive metabolites: CYP4A, the key enzyme in the formation of 20-hydroxyeicosatetraenoic acid, and the soluble epoxide hydrolase, which is responsible for the degradation of the vasodilator metabolites such as epoxyeicosatetraenoic acids. Effect of SF on kidney expression of CYP4A was investigated by immunoblotting. Results. We found that treatment with SF leads to significant reductions in both, the expression and activity of renal CYP4A isozymes, as well as the activity of soluble epoxide hydrolase (sEH). Consistent with these data, we have found that treatment with SF resisted the progressive rise in MAP in the developing SHR in a dose-dependent manner. Conclusion. This is the first demonstration that SF modulates the metabolism of AA by both P450 enzymes and sEH in SHR rats. This may represent a novel mechanism by which SF protects SHR rats against the progressive rise in blood pressure.

Paracrine Modulation of Baroreceptor Activity by Vascular Endothelium

Physiology ◽  
1991 ◽  
Vol 6 (5) ◽  
pp. 210-214
Author(s):  
MW Chapleau ◽  
G Hajduczok ◽  
FM Abboud
Keyword(s):  
Blood Pressure ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Arterial Blood Pressure ◽  
Vascular Endothelium ◽  
Cell Function ◽  
Endothelial Cell Function ◽  
Arterial Baroreceptors ◽  
Arterial Blood

Arterial baroreceptors are stimulated by vascular stretch and serve to buffer fluctuations in arterial blood pressure. Factors released from endothelial cells act in a paracrine manner to modulate sensitivity of baroreceptors. Impaired endothelial cell function contributes to resetting and decreased sensitivity of baroreceptors in pathological states such as hypertension.

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