Background Atrial fibrillation (AF) represents the most common arrhythmia leading to increased morbidity and mortality, yet, current treatment strategies have proven inadequate. Conventional treatment with antiarrhythmic drugs carries a high risk for proarrhythmias. The soluble epoxide hydrolase enzyme (sEH) catalyzes the hydrolysis of anti-inflammatory epoxy fatty acids including epoxyeicosatrienoic acids (EETs) from arachidonic acid to the corresponding pro-inflammatory diols. Therefore, the goal of the study is to directly test the hypotheses that inhibition of the sEH enzyme can result in an increase in the levels of EETs leading to the attenuation of atrial structural and electrical remodeling and the prevention of AF. Methods and Results For the first time, we report findings that inhibition of sEH reduces inflammation, oxidative stress, atrial structural and electrical remodeling. Treatment with sEH inhibitor significantly reduces the activation of key inflammatory signaling molecules, including the transcription factor nuclear factor κ-light-chain-enhancer (NF-κB), mitogen-activated protein kinase (MAPK) and transforming growth factor-β (TGF-β). Conclusions This study provides insights into the underlying molecular mechanisms leading to AF by inflammation and represents a paradigm shift from conventional antiarrhythmic drugs which block downstream events to a novel upstream therapeutic target by counteracting the inflammatory processes in AF.

The feasibility of monitoring intracellular sodium changes using Na triple quantum filtered NMR without a chemical shift reagent (SR) was investigated in an isolated rat heart during a variety of interventions for Na(i) loading. Perfusion with 1 mM ouabain or without K+ present in the perfusate for 30 min produced a rise of the Na TQF signal with a plateau of approximately 190% and approximately 228% relative to the preintervention level, respectively. Stop-flow ischemia for 30 min resulted in a TQF signal growth of approximately 147%. The maximal Na TQF signal increase of 460% was achieved by perfusion without K+/Ca2+, corresponding to an elimination of the Na transmembrane gradient. The observed values of Na NMR TQF growth in the physiological and pathological ranges are in agreement with reported data by other methods and have a linear correlation with intracellular sodium content as determined in this study by Co-EDTA method and by sucrose-histidine washout of the extracellular space. Our data indicate that the increase in Na TQF NMR signal is determined by the growth of Na(i), and the extracellular Na contribution to the total TQF signal is unchanged at approximately 64%. In conclusion, Na TQF NMR without using SR offers a unique and noninvasive opportunity to monitor alterations of intracellular sodium. It may provide valuable insights for developing cardioprotective strategies and for observing the effects of pharmaceutical treatments on sodium homeostasis.

Cardiac progenitor cells (CPCs) are multipotent cells that may offer tremendous potentials for the regeneration of injured myocardium. To expand the limited number of CPCs for effective clinical regeneration of myocardium, it is important to understand their proliferative potentials. Single-cell based assays were utilized to purify c-kitpos CPCs from human and mouse hearts. MicroRNA profiling identified eight differentially expressed microRNAs in CPCs from neonatal and adult hearts. Notably, the predicted protein targets were predominantly involved in cellular proliferation-related pathways. To directly test this phenotypic prediction, the developmental variance in the proliferation of CPCs was tested. Ki67 protein expression and DNA kinetics were tested in human and mouse in vivo CPCs, and doubling times were tested in primary culture of mouse CPCs. The human embryonic and mouse neonatal CPCs showed a six-fold increase in Ki67 expressing cells, a two-fold increase in the number of cells in S/G2-M phases of cell cycle, and a seven-fold increase in the doubling time in culture when compared to the corresponding adult CPCs. The over-expression of miR-17-92 increased the proliferation in adult CPCs in vivo by two-fold. In addition, the level of retinoblastoma-like 2 (Rbl2/p130) protein was two-fold higher in adult compared to neonatal-mouse CPCs. In conclusion, we demonstrate a differentially regulated cohort of microRNAs that predicts differences in cellular proliferation in CPCs during postnatal development and target microRNAs that are involved in this transition. Our study provides new insights that may enhance the utilization of adult CPCs for regenerative therapy of the injured myocardium.

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The positive results of our program model indicate that these methodologies may be helpful to others attempting to address the worldwide shortage of cardiovascular care and particularly the complex interventions required in the management of congenital cardiovascular disease.