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

Abstract

Epoxyeicosatrienoic acids (EETs) and their analogs have been identified as potent antihypertensive compounds with cardio- and renoprotective actions. Here, we examined the effect of EET-A, an orally active EET analog, and c -AUCB, an inhibitor of the EETs degrading enzyme soluble epoxide hydrolase, on the progression of post-myocardial infarction (MI) heart failure (HF) in normotensive Hannover Sprague-Dawley (HanSD) and in heterozygous Ren-2 transgenic rats (TGR) with angiotensin II-dependent hypertension. Adult male rats (12 weeks old) were subjected to 60-min left anterior descending (LAD) coronary artery occlusion or sham (non-MI) operation. Animals were treated with EET-A and c -AUCB (10 and 1 mg/kg/day, respectively) in drinking water, given alone or combined for 5 weeks starting 24 h after MI induction. Left ventricle (LV) function and geometry were assessed by echocardiography before MI and during the progression of HF. At the end of the study, LV function was determined by catheterization and tissue samples were collected. Ischemic mortality due to the incidence of sustained ventricular fibrillation was significantly higher in TGR than in HanSD rats (35.4 and 17.7%, respectively). MI-induced HF markedly increased LV end-diastolic pressure (P ed ) and reduced fractional shortening (FS) and the peak rate of pressure development [+(dP/dt) max ] in untreated HanSD compared to sham (non-MI) group [P ed : 30.5 ± 3.3 vs. 9.7 ± 1.3 mmHg; FS: 11.1 ± 1.0 vs. 40.8 ± 0.5%; +(dP/dt) max : 3890 ± 291 vs. 5947 ± 309 mmHg/s]. EET-A and c -AUCB, given alone, tended to improve LV function parameters in HanSD rats. Their combination amplified the cardioprotective effect of single therapy and reached significant differences compared to untreated HanSD controls [P ed : 19.4 ± 2.2 mmHg; FS: 14.9 ± 1.0%; +(dP/dt) max : 5278 ± 255 mmHg/s]. In TGR, MI resulted in the impairment of LV function like HanSD rats. All treatments reduced the increased level of albuminuria in TGR compared to untreated MI group, but neither single nor combined EET-based therapy improved LV function. Our results indicate that EET-based therapy attenuates the progression of post-MI HF in HanSD, but not in TGR, even though they exhibited renoprotective action in TGR hypertensive rats.

Association of Epoxide Hydrolase 2 Gene Arg287Gln with the Risk for Primary Hypertension in Chinese

“…Furthermore, we have examined the association of R287Q variant with the enzyme activity of soluble epoxide hydrolase and found a significant lower level of the 11,12-DHET in the mutation group than in the wild-type group. Our findings are biologically plausible, as soluble epoxide hydrolase is an enzyme responsible for rapid conversion of cytochrome P450 arachidonic acid epoxygenase metabolites, to inactive or less active DHETs [23,24]. For practical reasons, our findings represent a novel approach to understanding molecular mechanisms involved in the pathogenesis of hypertension and may help target therapies according to the genotypes of R287Q variant for patients with primary hypertension to optimize prevention strategies.…”

Epoxyeicosatrienoic acid analog EET-B attenuates post-myocardial infarction remodeling in spontaneously hypertensive rats

“…In addition, the improved post-MI LV function is more likely attributable to EET-B beneficial actions during CHF progression as it was previously demonstrated for other EET-based pharmacological interventions [ 8 , 10 , 11 , 18 , 37 , 48 ]. Finally, in a recent work we demonstrated that sEH inhibitor c-AUCB and EET analog EET-A, given alone or in combination at reperfusion attenuated the progression of post-MI LV systolic dysfunction only in Sprague-Dawley but not in hypertensive Ren-2 transgenic rats in spite of blood pressure reduction [ 19 , 49 ]. Moreover, these findings support previous findings indicating that the protective action of EET analogs against various cardiovascular diseases is independent of their antihypertensive actions.…”

Mitochondrial Dysfunction and Inflammaging in Heart Failure: Novel Roles of CYP-Derived Epoxylipids

“…Over the past decade, experimental studies have demonstrated EETs mediate a myriad of cellular and metabolic pathways, which are cardioprotective toward several pathologies including HF [ 187 , 188 , 189 , 190 ]. For instance, Cao et al reported that using ( S )-2-(11-(nonyloxy) undec-8( Z )-enamido) succinic acid (NUDSA), an EET agonist, in a murine model of myocardial infarction (MI) is associated with improved systolic dysfunction, decreased myocardial fibrosis and limited remodeling in post-infarcted HF [ 191 ].…”

“…Novel pharmacological approaches that selectively inhibit sEH have evolved as clinical tools in various cardiovascular diseases, including hypertension, cerebral ischemia, cardiac ischemia, cardiac hypertrophy, myocardial infarction and atherosclerosis [ 202 , 203 , 204 , 205 , 206 , 207 ]. Pharmacological sEH inhibition is demonstrated to improve both LV diastolic and systolic function and attenuate myocardial remodeling in established HF [ 188 , 208 , 209 ]. Treatment with cis -4-[4-(3-adamantan-1-yl-ureido) cyclohexyloxy] benzoic acid (c-AUCB)-attenuated increased systolic and diastolic LV cavity diameter following ischemia/reperfusion injury in rats.…”

“…Treatment with cis -4-[4-(3-adamantan-1-yl-ureido) cyclohexyloxy] benzoic acid (c-AUCB)-attenuated increased systolic and diastolic LV cavity diameter following ischemia/reperfusion injury in rats. Interestingly, the combined administration of EET mimetic and c-AUCB amplified the cardioprotective effects of the single therapy and significantly decreased the MI-induced chamber dilation accompanied with improved systolic function [ 188 ]. Chronic inhibition of sEH substantially attenuated lung congestion and albuminuria parallel to preserved cardiac function and structure, acknowledging sEH as a therapeutic target for the treatment of HF associated with chronic kidney disease [ 210 , 211 ].…”