Myocardial infarction leads to a loss of cardiac tissue, which is then replaced by fibrosis. Following this loss in adult mammals, pathological hypertrophy takes place and leads to heart failure. Zebrafish are able to regenerate their heart after an injury at all stages of life. Mammals also have this ability during the early stages of life but this process seems to be inhibited during adulthood in favour of an antagonist pathway: the hypertrophic response. Based on this paradigm, we believe that factors which induce hypertrophy in mammals will most likely induce cardiomyocyte proliferation and regeneration in adult zebrafish. One of these factors is KCNK2, a member of the two-pore-domain potassium (K2P) channels, which was recently associated with cardiac ischemia and pathological hypertrophy.

This study aims to characterise the zebrafish orthologs of KCNK2 and determine their role during heart regeneration in zebrafish.

Chemical inhibition combined with a zebrafish conditional line expressing a dominant negative isoform of Kcnk2 in the cardiomyocytes were used. The hearts were extracted at different time points after ventricular amputation to be fixed, sectioned and stained, using BrdU to assess proliferation, or AFOG to assess the presence/absence of a scar. Both channels were characterised in HEK-293 cells using patch clamp technic.

Electrophysiological analysis of zebrafish Kcnk2 orthologs showed that, like their human counterpart, they are activated by mechanical stretch, polyunsaturated fatty acids and intracellular acidification and they are expressed in cardiomyocytes. Using a specific antagonist and our transgenic line, we also showed that inhibition of Kcnk2 function leads to impaired heart regeneration.

We identified two zebrafish orthologs of KCNK2 sharing the same properties as human KCNK2. During heart regeneration in vivo, Kcnk2 inhibition seems to inhibit regeneration in zebrafish.