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Calcineurin Critical to Healthy Heart Function

Researchers have reported the first-ever data to show that the enzyme calcineurin is critical to controlling normal development and function of heart cells, and that loss of the protein leads to heart problems and death in genetically modified mice. The near total absence of calcineurin in these experimental mice led to heart arrhythmia, failure, and death, according to the research team. This report was selected as the paper of the week for the February 26, 2010 issue of the Journal of Biological Chemistry and was published online on February 19. Calcineurin is a protein phosphatase that is uniquely regulated by sustained increases in intracellular calcium ions following signal transduction events. Calcineurin is known to control cellular proliferation, differentiation, apoptosis, and inducible gene expression following stress and neuroendocrine stimulation. In the adult heart, calcineurin has earlier been shown to regulate hypertrophic growth of cardiomyocytes in response to pathologic insults that are associated with altered Ca2+ handling. It was previously known that calcineurin is important to heart function, but the extent of its role had not been defined prior to the current study. Although the current research involved mice, it nevertheless offers important insights for future studies that could lead to new approaches in diagnosis and treatment of heart patients, said Dr. Marjorie Maillet, the study's lead author and a researcher in the laboratory of senior author Dr. Jeffery Molkentin, at the Cincinnati Children’s Hospital Medical Center. In their work, the researches determined that calcineurin signaling is directly linked to the proper control of cardiac contractility, rhythm, and the expression of Ca2+-handling genes in the heart. These results reveal multiple mechanisms whereby calcineurin regulates cardiac development and myocyte contractility.

"We found that when you eliminate calcineurin, a pool of genes that regulates calcium in the heart went awry. This leads to defects in the growth and proliferation of heart cells, heart disease, arrhythmia, loss of contractility, and heart failure and disease," said Dr. Maillet.

Calcium is also important to cardiac growth and the contraction of heart muscle. Previous studies have linked abnormalities in calcium handling to cardiac disease, especially in adults. In mice genetically bred for calcineurin deficiency, the researchers saw that this deficiency causes a dramatic reduction in the expression of genes that coordinately regulate calcium-handling and contraction.

The scientists also reported a newly identified "feed-forward" mechanism, in which the direct activation of calcineurin by calcium augments the expression of genes that regulate calcium-handling proteins in the heart. [Press release] [JBC Paper of the Week summary] [JBC abstract]