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.

Keywords: chronic heart failure; echocardiography; epoxyeicosatrienoic acid; hypertension; myocardial infarction; soluble epoxide hydrolase.

FIGURE 1

Body weight of Hannover Sprague-Dawley (HanSD; A) and Ren-2 transgenic rats (TGR; B) before myocardial infarction (MI) and during 5 weeks of post-MI period and in Sham (non-MI) operated animals. Rats were treated with epoxyeicosatrienoic acid analog (EET-A) or soluble epoxide hydrolase inhibitor (c-AUCB), given alone or combined. The incidence of sustained ventricular fibrillation during ischemia (C) and 24 h survival rate (D) in HanSD and TGR subjected to MI. Values are means ± SEM. ^#P < 0.05 vs. HanSD.

FIGURE 2

Albumine/Creatinine clearance (A) and the total index of kidney injury (the sum of glomerulosclerosis and cortical tubulointerstitial injury; B) in Hannover Sprague-Dawley (HanSD) and Ren-2 transgenic rats (TGR) subjected to sham operation (non-MI) or myocardial infarction (MI) and treated with epoxyeicosatrienoic acid analog (EET-A) or soluble epoxide hydrolase inhibitor (c-AUCB), given alone or combined for 5 weeks since 24 h after MI. Values are means ± SEM; ^†P < 0.05 MI vs. corresponding Sham (non-MI) group; ^∗P < 0.05 vs. corresponding MI group.

FIGURE 3

Fractional shortening in Hannover Sprague-Dawley (HanSD) and Ren-2 transgenic rats (TGR) subjected to Sham (non-MI) operation or myocardial infarction (MI) and treated with epoxyeicosatrienoic acid analog (EET-A) or soluble epoxide hydrolase inhibitor (c-AUCB), given alone or combined for 5 weeks since 24 h after MI. Values are means ± SEM; ^†P < 0.05 MI vs. corresponding Sham (non-MI) group; ^∗P < 0.05 vs. corresponding MI group.

FIGURE 4

Left ventricle peak rates of pressure development and fall (A), developed pressure (B), and end-diastolic pressure (C) in Hannover Sprague-Dawley (HanSD) and Ren-2 transgenic rats (TGR) subjected to Sham (non-MI) operation or myocardial infarction (MI) and treated with epoxyeicosatrienoic acid analog (EET-A) or soluble epoxide hydrolase inhibitor (c-AUCB), given alone or combined for 5 weeks since 24 h after MI. Values are means ± SEM; ^†P < 0.05 MI vs. corresponding Sham (non-MI) group; ^∗P < 0.05 vs. corresponding MI group.