Their new study, published in the Journal of Biological Chemistry, demonstrates that calcineurin in hearts of mice is directly linked to proper cardiac muscle contraction, rhythm and maintenance of heart activity. The near total absence of calcineurin in mice leads to heart arrhythmia, failure and death, according to the research team.
Scientists knew previously that calcineurin is important to heart function, but the extent of its role had not been defined prior to the current study. Although the research involved mice, it offers important insights for future studies that could lead to new approaches in diagnosis and treatment of heart patients, said Marjorie Maillet, Ph.D., the study's first author.
"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 report 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.
Dr. Maillet works in the laboratory of the study's senior investigator, Jeffery Molkentin, Ph.D., a researcher in the division of Molecular Cardiovascular Biology at Cincinnati Children's and a Howard Hughes Medical Institute Investigator. Dr. Molkentin's laboratory and division are also part of the Cincinnati Children's Heart Institute.
Citation: Maillet et al., 'Heart-specific Deletion of CnB1 Reveals Multiple Mechanisms Whereby Calcineurin Regulates Cardiac Growth and Function', Journal of Biological Chemistry, January 2010, 285, 6716-6724; doi:10.1074/jbc.M109.056143
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