August 2014

The enzyme calcium/calmodulin-dependent kinase II (CaMKII) is a protein kinase that binds to other phosphate groups (phosphorylation) thereby influencing the activity of these molecules. The enzyme calcineurin is a phosphatase that, in contrast, cleaves phosphate groups on other molecules (dephosphorylation) and in doing so likewise influences molecular activity. The role of both molecules in heart disease has been studied intensively over the last 20 years. There is strong evidence that CaMKII and calcineurin, both of which are activated by calcium-dependent mechanisms, are key enzymes in the genesis and progression of chronic heart failure. However, there are conflicting findings on whether the experimental over-activation of these enzymes or the activation of enzymes present in the heart muscle cells alone is sufficient to induce the disease process. The authors of this study used for the first time a new genetic mouse model in which all CaMKII genes in the heart were switched off so that no CaMKII activity could be detected in the heart muscle cells. This allowed them to determine which target molecules are specifically phosphorylated by CaMKII. Among other things, the researchers found that CaMKII mediates phosphorylation of calcineurin and in doing so inhibits calcineurin. In the hearts of mice lacking CaMKII activity a corresponding activation of the calcineurin present in the cardiomyocytes was observed. This led to growth of the heart muscle. The surprising new finding is that despite calcineurin-mediated growth of the heart muscle, improved cardiac function and fewer pathological remodeling processes were observed when the heart was subjected to pressure loading. Based on these findings, the team of authors led by Johannes Backs from the DZHK partner site Heidelberg/Mannheim came to the conclusion that the inhibition of CaMKII but not of calcineurin is a promising approach in the treatment of chronic heart failure.

Link to the Paper