Original Research ArticleInhibition of soluble epoxide hydrolase reduces portal pressure by protecting mesenteric artery myogenic responses in cirrhotic rats
Introduction
Progression of hepatic vascular resistance and impairment of intrahepatic microcirculation contributes to the formation of portal hypertension (PHT) [1], setting the stage for esophageal variceal bleeding [2]. Hyperdynamic circulation has been shown to be a major factor in chronic portal hypertension in a portal-hypertensive rat model [3]. Several explanations for splanchnic vasodilatation have been put forward, including an excess of locally released vasodilator factors such as nitric oxide (NO) [4], [5], prostacyclin [4], [5], and carbon monoxide [6]. Although NO has been implicated in vascular hyporeactivity/vasodilatation in portal hypertension [5], [7], some studies found that splanchnic vasodilatation was related to epoxyeicosatrienoic acids (EETs) [8].
Arachidonic acid (AA) is metabolized by cytochrome P450 epoxygenase, generating endothelial EETs. EETs have been proposed to relax mesenteric arteries in cardiovascular diseases as endothelium-derived hyperpolarizing factors (EDHFs) [9]. EETs are hydrolyzed by sEH (soluble epoxide hydrolase) to less-vasoactive corresponding dihydroxyeicosatrienoic acids (DHETs) [10].
sEH inhibition may ameliorate carbon tetrachloride (CCl4)-induced liver fibrosis by endoplasmic reticulum stress [11], but the role of sEH in the modulation of pressure-induced vasodilation of the cirrhotic hyperdynamic circulation remains unknown. A previous study demonstrated that increased EETs decreased endothelial NO synthesis in the mesenteric arteries of sEH-knockout (KO) mice, but the interaction between EETs/sEH/sEH inhibitors (sEHIs) and NO in cirrhotic hyperdynamic circulation has not been investigated [12].
Myogenic response underlies the ability of arterioles to contract in response to increased endovascular pressure, and impaired tone may cause the vascular dysfunction associated with disease development [13]. In portal hypertension, mesenteric circulation constitutes the main hyperdynamic circulation [14]. However, the myogenic response of mesenteric arteries in portal hypertension has not been explored in detail.
We proposed that elevating endothelial EET levels, diminishing their degradation by sEHI may partly reverse the attenuated myogenic response of mesenteric arteries in cirrhotic rats. We also hypothesized that altering the balance between EETs and NO may account for hyperdynamic circulation.
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Compliance with ethical requirements
The study protocol, animal maintenance, and experimental procedures were approved by the local animal ethics committee of the Ninth Hospital and conducted in accordance with the guidelines of the Laboratory Animal Care and Use Committee at the School of Medicine, Shanghai Jiao Tong University (Shanghai, China). All institutional and national guidelines for the care and use of laboratory animals were followed.
Animal protocol
Experiments were performed on male Sprague-Dawley rats (265–300 g body weight) purchased
t-TUCB reduced portal pressure in CCl4-induced cirrhosis rats
Portal pressure, blood pressure (BP), body weight (BW), and heart rate (HR) are listed in Table 1. Currently, in vivo studies of liver cirrhosis have not directly assessed the impact of sEHI on portal pressure and hemorrhage risk. We found that the portal pressure of CCl4-induced cirrhotic rats was reduced by oral administration of t-TUCB (18.91 ± 1.11 mmHg vs. 14.34 ± 1.16 mmHg). BP and HR did not differ among the three groups. The decrease in BW was probably due to the CCl4, and was in accordance
Discussion
The inhibition of sEH increased the EETs/DHETs ratio in cirrhotic mesenteric arteries, and reduced portal pressure by protecting the myogenic response. Thus, the up-regulation of the EETs/DHETs ratio may explain why the inhibition of sEH reduced portal pressure. However, the EETs/DHETs ratio increased in the cirrhotic mesenteric arteries and t-TUCB further increased it by inhibiting hydrolysis of EETs (Fig. 2B–D). An increased EETs/DHETs ratio alone cannot explain a decrease in portal pressure
Conclusion
The present study showed that inhibition of sEH reduced portal pressure in cirrhotic rats by protecting the myogenic constriction of mesenteric arteries. Inhibition of sEH protected the impaired myogenic response by decreasing endothelial NO synthesis, while the imbalance of EETs and NO may account for the pathological cause of hyperdynamic circulation. sEHI intervention in cirrhotic hyperdynamic circulation may provide a novel approach in treating liver cirrhosis.
Conflicts of interest
The authors declare that they have no competing financial interests.
Acknowledgement
This study was supported by a grant from the Nature Science Foundation of China (No. 81370548).
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2021, Life SciencesCitation Excerpt :LC-MS/MS was used to measure EETs production in the mesenteric arteries. As previous description [16], we extracted phospholipids from vessel samples using the Bligh-Dyer method [17]. EETs were extracted using ethyl acetate (Sigma-Aldrich, St. Louis, MO, USA) after alkali hydrolysis of the phospholipids to release esterified EETs.
Soluble epoxide hydrolase inhibition with t-TUCB alleviates liver fibrosis and portal pressure in carbon tetrachloride-induced cirrhosis in rats
2018, Clinics and Research in Hepatology and GastroenterologyCitation Excerpt :Epoxyeicosatrienoic acids (EETs) and related epoxy fatty acids (EpFA), possess diverse protective effects in body, including anti-inflammation, anti-oxidation, anti-fibrosis and anti-tumor. They are enzymatically hydrolyzed by soluble epoxide hydrolase (sEH), generating inactive or less active dihydroxy molecules [7]. These diols formed from the EETs is still an open area of investigation and have been shown to have some pro-inflammatory activity.
Inhibition of soluble epoxide hydrolase lowers portal hypertension in cirrhotic rats by ameliorating endothelial dysfunction and liver fibrosis
2017, Prostaglandins and Other Lipid MediatorsCitation Excerpt :If any viability or stability criteria were not satisfied, the experiment was discarded. The quantification of hepatic tissue EETs by LC–MS/MS was performed as previous description [17]. EETs and DHETs were extracted with ethyl acetate(Sigma, USA) following alkali hydrolysis of the phospholipids to release esterified EETs and quantified with a Q-trap 3200 linear ion trap quadruple LC/MS/MS (ABScieX; Q-trap 3200) equipped with a Turbo V ion source operated in negative electrospray mode (Applied Biosystems, Foster City, CA), according to the instruction.
Advances in therapeutic options for portal hypertension
2018, Therapeutic Advances in Gastroenterology
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These authors contributed equally to this work.