NEW YORK (Reuters Health) - Mutations in Nkx2-5, a cardiac homeobox gene, have been linked to congenital heart disease, and now researchers have uncovered a mechanistic pathway that mediates this association. The findings indicate a possible point of therapeutic intervention.
To define the pathways involved, Dr. Kenneth R. Chien, from the University of California at San Diego, and colleagues created mice lacking Nkx2-5 just in ventricular muscle cells; complete global knockout of the gene has been shown to be fatal.
The researchers’ findings are reported in the April 30th issue of Cell.
Although the animals showed no structural cardiac defects, they did have progressive complete heart block and displayed trabecular muscle overgrowth similar to that seen in patients with Nkx2-5 mutations.
At birth, the mice were noted to have a hypoplastic atrioventricular node. Later, selective dropout of the conducting cardiomyocytes occurred, the researchers report. Further analysis revealed aberrant expression of certain atrial and conduction system-restricted target genes.
The researchers also found high expression of BMP-10, an important regulator of cardiac morphogenesis. This overexpression was associated with myocardial overgrowth and hypertrabeculation.
“Loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease,” the authors note.
“It will become of interest to determine if antagonism of chronic BMP-10 signals may represent a new therapeutic approach to prevent progressive cardiac defects in genetic forms of human congenital heart disease,” they add.
Source: Cell 2004;117:373-386. [ Google search on this article ]
MeSH Headings:Genes, Homeobox: Heart Defects, CongenitalCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.