Tissue fibrosis represents one of the largest groups of diseases for which there are very few effective therapies. In the heart, myocardial infarction (MI) resulting in the loss of cardiac myocytes can culminate in adverse cardiac remodeling leading to eventual heart failure. Adverse cardiac remodeling includes myocyte hypertrophy, fibrosis, and electrical remodeling. We have previously demonstrated the beneficial effects of several potent soluble epoxide hydrolase inhibitors (sEHIs) in different models of cardiac hypertrophy and failure. Here, we directly determine the molecular mechanisms underlying the beneficial effects of sEHIs in cardiac remodeling post-MI. Treatment with a potent sEHI, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU), which was started 1 wk post-MI in a murine model, results in a significant improvement in cardiac function. Importantly, treatment with TPPU results in a decrease in cardiac fibrosis as quantified using histological and immunostaining techniques. Moreover, single-cell-based assays demonstrate that treatment with TPPU results in a significant decrease not only in the percentages but also the proliferative capacity of different populations of cardiac fibroblasts as well as a reduction in the migration of fibroblasts into the heart from the bone marrow. Our study provides evidence for a possible unique therapeutic strategy to reduce cardiac fibrosis and improve cardiac function post-MI.

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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.

Rationale Adenylyl cyclase (AC) represents one of the principal molecules in the β-adrenergic receptor (βAR) signaling pathway, responsible for the conversion of ATP to the second messenger, cAMP. AC type 5 (ACV) and 6 (ACVI) are the two main isoforms in the heart. While highly homologous in sequence, these two proteins nevertheless play different roles during the development of heart failure. Caveolin-3 is a scaffolding protein, integrating many intracellular signaling molecules in specialized areas called caveolae. In cardiomyocytes, caveolin is predominantly located along invaginations of the cell membrane known as t-tubules. Objective We take advantage of ACV and ACVI knockout mouse models to test the hypothesis that there is distinct compartmentalization of these two isoforms in ventricular myocytes. Methods and Results We demonstrate that ACV and ACVI isoforms exhibit distinct subcellular localization. ACVI isoform is localized in the plasma membrane outside of the t-tubular region, and is responsible for β1AR signaling-mediated enhancement of the L-type Ca2+ current (ICa,L) in ventricular myocytes. In contrast, ACV isoform is localized mainly in the t-tubular region where its influence on ICa,L is restricted by phosphodiesterase (PDE). We further demonstrate that the interaction between caveolin-3 with ACV and PDE is responsible for the compartmentalization of ACV signaling. Conclusions Our results provide new insights into the compartmentalization of the two AC isoforms in the regulation of ICa,L in ventricular myocytes. Since caveolae are found in most mammalian cells, the mechanism of βAR and AC compartmentalization may also be important for βAR signaling in other cell types.

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