Area of Research

• Our laboratory was the first to identify several isoforms of small conductance Ca2+-activated K+ channels (SK channels) that underlie Ca2+-activated K+ current in human and mouse atrial myocytes. Even though the roles of these channels have been extensively investigated in neurons, their roles in the heart are only beginning to be recognized. We demonstrated that the channels are highly expressed in atrial compared to ventricular tissues. Null mutation of the SK2 channels results in atrial arrhythmias and AV node dysfunction. Subsequently, our findings have been supported by several different laboratories. Even more relevant to translational medicine is the finding from recent studies using genome-wide association analysis that has provided a genetic link between SK channel polymorphisms and lone atrial fibrillation (AF) in humans. Our studies have unmasked a functional crosstalk between Cav1.3 and SK channels. We have obtained new evidence to demonstrate that the expression of several interacting proteins, -actinin2, myosin light chain 2, and filamin A, are required for the proper membrane localization of SK channels. Even more exciting is the finding that an increase in intracellular Ca2+, as seen in AF, results in an increase in membrane localization of SK channels which would be predicted to lead to a decrease in effective refractory periods, an increase in functional reentry, and the maintenance of atrial arrhythmias. 

  Our efforts thus far have paid off. Recent studies from several laboratories have provided additional support for the importance of SK channels. Indeed, SK channels may represent a novel drug target for AF. Insights into the molecular interactions between these new classes of cardiac ion channels are likely to be highly significant clinically. Thus, our studies have provided unique insights regarding the roles of these newly described channels in the heart. 

  Our laboratory was the first to demonstrate beneficial effects of a novel class of soluble epoxide hydrolase (sEH) inhibitors in cardiac hypertrophy, failure and arrhythmias. This work is a collaborative effort with Dr. Hammock at UC Davis. Treatment with sEH inhibitors (sEHIs) results in the prevention of ventricular myocyte hypertrophy and electrical remodeling in pressure overload and myocardial infarction models. We further demonstrate that treatment with sEHIs prevents cardiac fibroblast (CF) proliferation and fibrosis. These results are exciting because they demonstrate broader salutary effects in cardiac remodeling (not limited to myocyte hypertrophy alone) of this novel class of compounds. sEHIs have been shown to potently block the catalytic conversion of epoxyeicosatrienoic acids (EETs) to the corresponding dihydroxyeicosatrienoic acids (DHETs). EETs are products of cytochrome P450 epoxygenases that are known to have vasodilatory as well as anti-inflammatory properties. Since atrial fibrosis has been shown to play critical roles in atrial fibrillation, we are actively testing our hypothesis that treatment with sEHIs will be beneficial in the prevention of atrial fibrillation by reducing 1) atrial fibrosis, and 2) electrical remodeling in atrial myocytes.