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A novel soluble epoxide hydrolase vaccine protects murine cardiac muscle against myocardial infarction.

ABSTRACT: Myocardial infarction is still a life-threatening disease, even though its prognosis has been improved through the development of percutaneous coronary intervention and pharmacotherapy. In addition, heart failure due to remodeling after myocardial infarction requires lifelong management. The aim of this study was to develop a novel treatment suppressing the myocardial damage done by myocardial infarction. We focused on inhibition of soluble epoxide hydrolase to prolong the activation of epoxyeicosatrienoic acids, which have vasodilatory and anti-inflammatory properties. We successfully made a new vaccine to inactivate soluble epoxide hydrolase, and we have evaluated the effect of the vaccine in a rat myocardial infarction model. In the vaccinated group, the ischemic area was significantly reduced, and cardiac function was significantly preserved. Vaccine treatment clearly increased microvessels in the border area and suppressed fibrosis secondary to myocardial infarction. This soluble epoxide hydrolase vaccine is a novel treatment for improving cardiac function following myocardial infarction.

SUBMITTER: Kitsuka T

PROVIDER: S-EPMC9051153 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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A novel soluble epoxide hydrolase vaccine protects murine cardiac muscle against myocardial infarction.

Kitsuka Takahiro T Shiraki Aya A Oyama Jun-Ichi JI Nakagami Hironori H Tanaka Atsushi A Node Koichi K

Scientific reports 20220428 1

Myocardial infarction is still a life-threatening disease, even though its prognosis has been improved through the development of percutaneous coronary intervention and pharmacotherapy. In addition, heart failure due to remodeling after myocardial infarction requires lifelong management. The aim of this study was to develop a novel treatment suppressing the myocardial damage done by myocardial infarction. We focused on inhibition of soluble epoxide hydrolase to prolong the activation of epoxyeic ...[more]

PMID: 35484372

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Project description:BackgroundIt has been demonstrated that soluble epoxide hydrolase inhibitors (sEHIs) are protective against ischemia-induced lethal arrhythmias, but the mechanisms involved are unknown. Previously, we showed that sEHIs might reduce the incidence of ischemic arrhythmias by suppressing microRNA-1 (miR-1) in the myocardium. As miR-1 and miR-133 have the same proarrhythmic effects in the heart, we assumed that the beneficial effects of sEHIs might also relate to the regulation of miR-133.MethodsA mouse model of myocardial infarction (MI) was established by ligating the coronary artery. The sEHI t-AUCB (trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid) was administered daily for 7 days before MI. Myocardial infarct size and cardiac function was assessed at 24 h post-MI. The miRNA expression profiles of sham and MI mice treated with or without t-AUCB were determined by microarray and verified by real-time PCR. The incidence of arrhythmias was assessed by in vivo electrophysiologic studies. The mRNA levels of miR-133, its target genes (KCNQ1 [potassium voltage-gated channel subfamily Q member 1] and KCNH2 [potassium voltage-gated channel subfamily H member 2]), and serum response factor (SRF) were measured by real-time PCR; KCNQ1, KCNH2, and SRF protein levels were assessed by western blotting.ResultsWe demonstrated that the treatment with sEHIs could reduce infarct size, improve cardia function, and prevent the development of cardiac arrhythmias in MI mice. The expression levels of 14 miRNAs differed between the sham and MI groups. t-AUCB treatment altered the expression of eight miRNAs: two were upregulated and six were downregulated. Of these, the muscle-specific miR-133 was downregulated in the ischemic myocardium. In line with this, up-regulation of miR-133 and down-regulation of KCNQ1 and KCNH2 mRNA/protein were observed in ischemic myocaridum, whereas administration of sEHIs produced an opposite effect. In addition, miR-133 overexpression inhibited expression of the target mRNA, whereas t-AUCB reversed the effects. Furthermore, SRF might participate in the negative regulation of miR-133 by t-AUCB.ConclusionsIn MI mice, sEHI t-AUCB can repress miR-133, consequently stimulating KCNQ1 and KCNH2 mRNA and protein expression, suggesting a possible mechanism for its potential therapeutic application in ischemic arrhythmias.

Dataset Information

A novel soluble epoxide hydrolase vaccine protects murine cardiac muscle against myocardial infarction.

Publications

A novel soluble epoxide hydrolase vaccine protects murine cardiac muscle against myocardial infarction.

Similar Datasets

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