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Big-hearted fish reveals genetics of cardiovascular condition
Date:2/25/2009

afish to develop enlarged hearts. Sensing that this observation could help unlock the mystery of what CCM proteins do, Kleaveland decided to see if these results could be extended to mice.

"Our notion was to take the zebrafish developmental studies and use the mouse as a way of bridging between what appeared to be a role in heart development in fish and blood vessel disease in people," says Kahn.

Kleaveland genetically engineered mice that both completely lack the HEG protein and produce diminished amounts of CCM2. This combination of genetic defects is fatal for the mice; they die during embryonic development. But, examination of their cardiovascular system and that of genetically altered fish, as well revealed several key findings, Kleaveland says.

First, loss of HEG produces cardiovascular defectsmainly leakinessin the heart, in blood vessels in the lung, and in the lymphatic system. Second, loss of HEG with partial loss of CCM2 produces a worse cardiovascular defectfailure to even form critical blood vessels. Third, all of these defects are characterized by malformed cell-cell junctions in the endothelial cells that line these organs. And finally, HEG actually physically interacts with CCM proteins.

"It looks like the disease is a reflection of a disruption in endothelial cell-cell junctions, and this pathway is required to regulate them," Kahn says.

These data underscore the evolutionary significance of the biochemical process underlying CCM. "With millions of years of evolution between fish and mammals, genes typically acquire new roles and lose old roles," Kahn explains. "When things are that conserved, it just tends to mean that it's a highly important and central process, and it probably also tells us that whatever it's doing is fundamental to blood vessels and the whole cardiovascular system."

The study, Kahn adds, addresses a debate in the field as to whether CCM is the result of defects that cause
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert  

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