Effects of Epoxyeicosatrienoic Acid-Enhancing Therapy on the Course of Congestive Heart Failure in Angiotensin II-Dependent Rat Hypertension: From mRNA Analysis towards Functional In Vivo Evaluation.

Petr Kala,Luděk Červenka,John R Falck,Matúš Miklovič,Miloš Táborský,Zdeňka Vaňourková,Janusz Sadowski,Josef Veselka,Petra Škaroupková,Vít Gloger,John D Imig,Hana Maxová,Marek Vícha,Renáta Aiglová,Elzbieta Kompanowska-Jezierska,Olga Gawrys,Šárka Jíchová

doi:10.3390/biomedicines9081053

Abstract

This study evaluates the effects of chronic treatment with EET-A, an orally active epoxyeicosatrienoic acid (EETs) analog, on the course of aorto-caval fistula (ACF)-induced heart failure (HF) in Ren-2 transgenic rats (TGR), a model characterized by hypertension and augmented activity of the renin-angiotensin system (RAS). The results were compared with standard pharmacological blockade of the RAS using angiotensin-converting enzyme inhibitor (ACEi). The rationale for employing EET-A as a new treatment approach is based on our findings that apart from increased RAS activity, untreated ACF TGR also shows kidney and left ventricle (LV) tissue deficiency of EETs. Untreated ACF TGR began to die 17 days after creating ACF and were all dead by day 84. The treatment with EET-A alone or ACEi alone improved the survival rate: in 156 days after ACF creation, it was 45.5% and 59.4%, respectively. The combined treatment with EET-A and ACEi appeared to improve the final survival to 71%; however, the difference from either single treatment regimen did not reach significance. Nevertheless, our findings support the notion that targeting the cytochrome P-450-dependent epoxygenase pathway of arachidonic acid metabolism should be considered for the treatment of HF.

Highlights

The expression of renin in the kidney was significantly reduced in sham-operated transgenic rats (TGR) and aorto-caval fistula (ACF) TGR when compared to sham-operated Hannover Sprague-Dawley (HanSD) (Supplementary Figure S1)
The ANG 1-7 levels were on the same level in sham-operated TGR as in control HanSD rats, which resulted in the impaired systemic and intrarenal balance between vasodilator and vasoconstrictor axes of the renin-angiotensin system (RAS) expressed as the ratio of ANG 1-7 to angiotensin II (ANG II) values (Supplementary Figure S2)
Despite the apparent limitations of this study, our data show that the ACF TGR in the early phase of high-output heart failure (HF) exhibits substantial tissue deficiency of EETs

Summary

Introduction

Biomedicines 2021, 9, 1053 than 1.1 million [1,2]. Despite an array of therapeutic approaches available and recent pharmacological advances, the prognosis in HF is still poor, worse than in common cancers [1,3,4,5,6]. New treatment strategies are urgently needed as well as focused experimental studies to evaluate the therapeutic effects of new therapeutic approaches. Recent research has been focused on the epoxyeicosatrienoic acids (EETs), the metabolites of cytochrome P-450 (CYP)-dependent epoxygenase pathway of arachidonic acid (AA). It was shown that EETs importantly contribute to the regulation of renal and cardiovascular function and exert antihypertensive and organ-protective actions [7,8,9,10]

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Results

Discussion

Conclusion