Soluble Epoxide Hydrolase Inhibitors Regulate Ischemic Arrhythmia by Targeting MicroRNA-1

Background: Soluble epoxide hydrolase inhibitors (sEHis) inhibit the degradation of epoxyeicosatrienoic acids (EETs) in cells, and EETs have antiarrhythmic effects. Our previous experiments confirmed that t-AUCB, a preparation of sEHis, inhibited ischemic arrhythmia by negatively regulating microRNA-1 (miR-1), but its specific mechanism remained unclear.Aim: This study aimed to examine the role of serum response factor (SRF) and the PI3K/Akt/GSK3β pathway in t-AUCB-mediated regulation of miR-1 and the interaction between them.Methods/Results: We used SRF small interfering RNA (siSRF), SRF small hairpin (shSRF) RNA sequence adenovirus, PI3K/Akt/GSK3β pathway inhibitors, t-AUCB, and 14,15-EEZE (a preparation of EETs antagonists) to treat mouse cardiomyocytes overexpressing miR-1 and mice with myocardial infarction (MI). We found that silencing SRF attenuated the effects on miR-1 and its target genes KCNJ2 and GJA1 in the presence of t-AUCB, and inhibition of the PI3K/Akt/GSK3β pathway antagonized the effects of t-AUCB on miR-1, KCNJ2, and GJA1, which were associated with PI3Kα, Akt, and Gsk3β but not PI3Kβ or PI3Kγ. Moreover, the PI3K/Akt/GSK3β pathway was involved in the regulation of SRF by t-AUCB, and silencing SRF inhibited the t-AUCB-induced increases in Akt and Gsk3β phosphorylation.Conclusions: Both the SRF and the PI3K/Akt/GSK3β pathway are involved in the t-AUCB-mediated regulation of miR-1, and these factors interact with each other.

Abstract 13053: Characteristics, Outcomes, and Predictors in Cardiovascular Shock Patients in Japan: Results From the Japanese Circulation Society Cardiovascular Shock Registry

Introduction: Despite the advances in the treatment of cardiogenic shock, mortality in these patients remains high. Data on the actual state of cardiovascular shock treatment and outcomes in Japan are scarce. In this study, we aimed to investigate the baseline characteristics and outcomes of patients with cardiovascular shock and identify the predictors of 30-day mortality. Methods: The Japanese Circulation Society Cardiovascular Shock registry was a prospective, observational, multi-center, cohort study. Between May 2012 and June 2014, a total of 980 patients with cardiovascular shock were enrolled from 82 centers in Japan. The median (interquartile range) age of the enrolled patients was 72 (63, 81) years, and 66% of the patients were male. The primary endpoint was all-cause death at 30 days. Results: The causes of shock included acute coronary syndrome (50.6%), non-ischemic arrhythmia (15.9%), aortic disease (14.9%), myocarditis (2.2%), cardiomyopathy (3.4%), pulmonary embolism (4.4%), valvular heart disease (1.3%), infective endocarditis (0.5%) and cardiac tamponade (1.4%). The all-cause mortality was 34.3%. On multivariate analysis, systolic blood pressure (odds ratio [OR], 0.986; 95% confidence interval [CI], 0.98-0.99, p<0.001), neurological status (OR, 1.694; 95% CI, 1.47-1.96, p<0.001), estimated glomerular filtration rate (OR, 0.982; 95% CI, 0.97-0.99, p<0.001), non-ischemic arrhythmia (OR, 0.516; 95% CI, 0.32-0.82, p=0.005), aortic disease (OR, 2.155; 95% CI, 1.41-3.30, p<0.001), and myocarditis (OR, 3.803; 95% CI, 1.41-10.23, p=0.008) were independent predictors of all-cause death at 30 days. Conclusion: Patients with non-ischemic arrhythmia had better prognosis, whereas those with aortic disease and myocarditis had poor prognosis. Blood pressure, neurological status, and renal function were also independent predictors of 30-day mortality.