Introduction: Myocardial Ischemia (MI), one of the major causes of heart failure, is associated with cardiac remodeling, insufficient angiogenesis and enhanced oxidative stress. Cytochrome P450 epoxygenase metabolites of arachidonic acid, EETs, have multiple cardiovascular effects, including vasodilation, inhibition of inflammatory response and stimulation of epithelial cell growth. In addition, emerging studies indicate a role of these unique lipid mediators in the regulation of metabolic homeostasis. We propose that EET agonists reduce post infarcted cardiac remodeling by improving cardiac dysfunction through increased angiogenesis improved cardiac energy metabolism and a reduction in oxidative stress.
Methods: C57B16 mice were divided into 3 groups: sham, mice with myocardial infarction (MI) via LAD ligation and mice with MI treated with an EET-agonist (NUDSA). NUDSA was administered after 5 days of MI (0.5 mg/kg) in C57B16 mice. Myocardial echocardiography was performed 30 days after MI to assess the cardiac function. Capillary density, oxidative stress and cardiac energy metabolism markers were compared among the groups.
Results: Echocardiography showed that left ventricle dilatation, measured as end diastolic area (EDA), was reduced in NUDSA treated groups compared to the MI group (C57, EDA: MI: 0.413 ±0.02 cm2; MI+NUDSA: 0.217±0.03 cm2; p<0.05). Cardiac Index, decreased by MI, was restored by NUDSA in C57 mice. Cardiac histological examination revealed an increase in myocardial angiogenesis and capillary density in mice treated with NUDSA (p<0.01 vs. MI). Cardiac tissue showed an increased expression of ETS-1, phosphorylated Acetyl CoA Carboxylase (pACC) and Carnitine Palmitoyl Transferase I (CPT-1) along with a decrease in 3NT and gpphox 91 expression in mice treated with NUDSA as compared to the MI group (p<0.05).
Conclusion: This is the first study to demonstrate that EET improves cardiac energy metabolism in infarcted heart by regulating fatty acid oxidation and ameliorating oxidative stress and cardiac remodeling. Thus pharmacological induction of EET may open new avenues in the treatment of patients with post infarcted heart failure.