Pharmacological Blockade of Soluble Epoxide Hydrolase Attenuates the Progression of Congestive Heart Failure Combined With Chronic Kidney Disease: Insights From Studies With Fawn-Hooded Hypertensive Rats

Abstract

An association between congestive heart failure (CHF) and chronic kidney disease (CKD) results in extremely poor patient survival rates. Previous studies have shown that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, improves the survival rate in CHF induced by aorto-caval fistula (ACF) and attenuates CKD progression. This prompted us to examine if sEH inhibitor treatment would improve the outcome if both experimental conditions are combined. Fawn-hooded hypertensive (FHH) rats, a genetic model showing early CKD development was employed, and CHF was induced by ACF. Treatment with an sEH inhibitor was initiated 4 weeks after ACF creation, in FHH and in fawn-hooded low-pressure (FHL) rats, a control strain without renal damage. The follow-up period was 20 weeks. We found that ACF FHH rats exhibited substantially lower survival rates (all the animals died by week 14) as compared with the 64% survival rate observed in ACF FHL rats. The former group showed pronounced albuminuria (almost 30-fold higher than in FHL) and reduced intrarenal EET concentrations. The sEH inhibitor treatment improved survival rate and distinctly reduced increases in albuminuria in ACF FHH and in ACF FHL rats, however, all the beneficial actions were more pronounced in the hypertensive strain. These data indicate that pharmacological blockade of sEH could be a novel therapeutic approach for the treatment of CHF, particularly under conditions when it is associated with CKD.

Renal Sympathetic Denervation Attenuates Congestive Heart Failure in Angiotensin II-Dependent Hypertension: Studies with Ren-2 Transgenic Hypertensive Rats with Aortocaval Fistula

“…Second, our hypothesis was that potential beneficial effects of RDN on the course of CHF in ACF TGR are dominantly mediated by improvement of renal function. We showed previously that RBF is decreased at the very early stage of compensation phase of ACF-induced CHF, and persistent renal dysfunction rather than progressing cardiac remodeling was responsible for the reduction in long-term survival rate [12, 13, 31, 44]. In addition, our recent study has suggested that altered renal vascular responsiveness, particularly exaggerated renal vascular responsiveness, to ANG II might play an important role in the development of renal dysfunction and can accelerate the decompensation of CHF in ACF TGR [14].…”

The Role of Epoxyeicosatrienoic Acids in Cardiac Remodeling

“…The effects of EETs in ACF-induced volume overload-related cardiac remodeling have been studied previously ( Cervenka et al, 2015a , b ; Sporkova et al, 2017 ; Kala et al, 2018 ; Vackova et al, 2019a , b ). It is demonstrated that the level of EETs is downregulated in the heart of ACF animals, while the expression of sEH is upregulated ( Cervenka et al, 2015a , b ).…”

Epoxyeicosatrienoic Acid-Based Therapy Attenuates the Progression of Postischemic Heart Failure in Normotensive Sprague-Dawley but Not in Hypertensive Ren-2 Transgenic Rats

“…On the other hand, another sEH inhibitor GSK2256294 did not reverse LV dysfunction induced by pressure overload in both mice and rats, in spite of the fact that the increased an EETs-to-DHETs ratio was observed (Morgan et al, 2013). Similarly, c -AUCB did not alter LV contractility in hypertensive TGR and Fawn-hooded rats as well as normotensive HanSD and Fawn-hooded low-pressure rats subjected to volume overload (Červenka et al, 2015a,b; Vacková et al, 2019).…”