Abstract 17427: Arachidonic Acid-Derived 14,15-Epoxyeicosatrienoic Acid Exerts Antihypertrophic Effects via Inhibition of Calcineurin Activation

Introduction: Epoxyeicosatrienoic acids (EETs) are epoxides derived from arachidonic acid catalyzed by an epoxygenase system. Although EETs have been shown to protect against ischemia little is known regarding their effects on the hypertrophic program. In this study we determined the direct effect of 14,15-EET on phenylephrine (PE)-induced hypertrophy in neonatal rat ventricular myocytes (NRVMs) as well as its effect on the postinfarction response in rats subjected to 4 weeks of sustained coronary artery ligation (CAL). Methods and Results: Treatment of NRVMs with 10 μM PE for 24 increased the cell surface area by 1.3 fold and ANP gene expression measured by real-time PCR by 1.8 fold (P<0.05 for both). These responses was associated with increased production of 14,15 EET by approximately 1.6 fold (P<0.05) determined by liquid chromatography-mass spectrometry. The hypertrophic response to PE was associated with significantly increased intracellular Na+ (1.75 fold) and Ca2+ (1.3 fold) levels which were prevented by 100 nM 14,15-EET. In addition, PE induced an increase in MCIP1 expression, an index of calcineurin activation by 2-fold (P<0.05) which was completely prevented by 14,15 EET. Post-CAL administration of 14,15-EET (3μg/kg bw/day) via osmotic minipump significantly improved left ventricular function as determined by echocardiography (ejection fraction: CAL+saline 57.48±2.18% vs CAL+EET 72.75±2.19%, fractional shortening: CAL+saline 34.03±2.07% vs CAL+EET 44.55±1.00%, E/A ratio: CAL+saline 2.21±0.17 vs CAL+EET 1.63±0.13). These effects were associated with significantly reduced left ventricular internal dimensions during diastole and systole (CAL + saline LVIDd 8.59±0.14 mm and LVIDs 5.15 ± 0.26 mm vs CAL+14,15-EET LVIDd 7.89 ± 0.1 mm and LVIDs 4.01 ± 0.24 mm). These effects were associated with significantly reduced indices of hypertrophy as well as abrogation in the 10-fold increase in MCIP1 expression. Conclusion: Our results demonstrate that 14,15-EET induces a marked antihypertrophic and antiremodelling effect likely by preventing calcineurin activation. Exogenous administration, enhancing its endogenous synthesis or preventing 14,15-EET degradation may represent effective heart failure treatment strategies.