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Background: Epoxyeicosatrienoic acids (EETs) are natural angiogenic mediators regulated by soluble epoxide hydrolase (sEH). Inhibitors of sEH can stabilize EETs levels and were reported to reduce atherosclerosis and inhibit myocardial infarction in animal models. In this work, we investigated whether increasing EETs with the sEH inhibitor t-AUCB would increase angiogenesis related function in endothelial progenitor cells (EPCs) from patients with acute myocardial infarction (AMI)., Methods and Results: EPCs were isolated from 50 AMI patients and 50 healthy subjects (control). EPCs were treated with different concentrations of t-AUCB for 24h with or without peroxisome proliferator activated receptor γ (PPARγ) inhibitor GW9662. Migration of EPCs was assayed in trans-well chambers. Angiogenesis assays were performed using a Matrigel-Matrix in vitro model. The expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α) mRNA and protein in EPCs was measured by real-time PCR or Western blot, respectively. Also, the concentration of EETs in the culture supernatant was detected by ELISA. The activity of EPCs in the AMI patient group was reduced compared to healthy controls. Whereas increasing EET levels with t-AUCB promoted a dose dependent angiogenesis and migration in EPCs from AMI patients. Additionally, the t-AUCB dose dependently increased the expression of the angiogenic factors VEGF and HIF-α. Lastly, we provide evidence that these effects were PPARγ dependent., Conclusion: The results demonstrate that the sEH inhibitor positively modulated the functions of EPCs in patients with AMI through the EETs-PPARγ pathway. The present study suggests the potential utility of sEHi in the therapy of ischemic heart disease., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: The development of cardiovascular disease has been linked to lowered levels of epoxyeicosatrienoic acids (EETs) in the cardiovascular system. Ischemic cardiomyopathy is caused by atherosclerotic lesions in multi-coronary arteries especially diffusive lesions, which can lead to severe myocardial dysfunction, heart enlargement, heart failure, or arrhythmia, and so on. The EETs are metabolized by the soluble epoxide hydrolase (sEH) encoded by the EPHX2 gene that has several known polymorphisms., Content: The EPHX2 gene polymorphism is associated with sEH catalytic activity and various cardiovascular diseases. sEH is distributed in a variety of organs and tissues and regulated by multiple factors. Research in the area has led to the presence of multiple powerful soluble epoxide hydrolase inhibitors (sEHIs), whose molecular structure and function has been optimized gradually. sEHIs increase EETs' concentration by inhibiting hydration of EETs into their corresponding vicinal diols. EETs are important signaling molecules and known as endothelium-derived hyperpolarizing factors (EDHF). sEHIs have been developed for their ability to prevent atherosclerosis, dilate the coronary artery, promote angiogenesis, ameliorate postischemic recovery of heart contractile function, decrease ischemia/reperfusion injury, modulate postischemic arrhythmia, and prevent heart failure., Summary: sEH is one of the etiological factors of cardiovascular diseases, and plays an important role in the progression of myocardium ischemia. This indicates that sEHIs provide a new method for the prevention and treatment of ischemic cardiomyopathy., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)