In this study, we reveal distinct protein kinase C (PKC)-dependent regulation of cardiac fibroblast transdifferentiation and proliferation and suggest that PKC agonists exhibit potential as an antifibrotic treatment.
Cardiac fibrosis is a pathological process that contributes to heart failure. Unfortunately, the molecular mechanisms regulating fibrosis in the heart are not yet fully understood, which hinders the development of new therapies. The PKC family of enzymes have been suggested to play a role in cardiac fibrosis, but the results have been conflicting. The potential of targeting PKC with pharmacological compounds to inhibit pathological fibrosis had not been thoroughly investigated before. Therefore, in this study we wanted to investigate the effect of pharmacological PKC activation and inhibition on cardiac fibroblast transdifferentiation and proliferation, two central processes in fibrosis.
We characterized mouse cardiac fibroblasts on gene, protein, and phenotypic level in response to PKC agonists and inhibitors, and revealed that PKC agonists both inhibit cardiac fibroblast transdifferentiation and decrease cardiac fibroblast proliferation. Moreover, we demonstrated that cardiac fibroblast transdifferentiation and proliferation are regulated via distinct PKC isoform subgroups: classical and novel isoforms, respectively. Overall, our results indicate that pharmacological PKC activation may be a promising strategy to inhibit myocardial fibrosis.