Scientists are reporting the first-ever data to show that the enzyme calcineurin is critical in controlling normal development and function of heart cells, and that loss of the protein leads to heart problems and death in genetically modified mice.
Published Feb. 26 in the Journal of Biological Chemistry as the paper of the week, and posted online Feb. 19, the research was led by scientists at Cincinnati Children's Hospital Medical Center and the Howard Hughes Medical Institute.
The study 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.
Also collaborating on the study were researchers from the University Paris-Sud, Châtenay-Malabry, France and the department of Molecular and Cellular Physiology at the University of Cincinnati College of Medicine.
Funding support for the study came from the National Institutes of Health, the Howard Hughes Medical Institute, the Ohio Valley Affiliate of the American Heart Association and a collaborative research grant in cardiovascular disease from the Fondation Leducq.
- Marjorie Maillet, Jennifer Davis, Mannix Auger-Messier, Allen York, Hanna Osinska, Jérôme Piquereau, John N. Lorenz, Jeffrey Robbins, Renée Ventura-Clapier, and Jeffery D. Molkentin. Heart-specific Deletion of CnB1 Reveals Multiple Mechanisms Whereby Calcineurin Regulates Cardiac Growth and Function. Journal of Biological Chemistry, 2010; 285: 6716-6724 DOI: 10.1074/jbc.M109.056143
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