Epigenetics and chromatin remodeling, it turns out, may play a role in heart disease. In one of two keynote addresses that opened the Keystone Symposia?s meeting on Molecular Mechanisms of Cardiac Disease and Regeneration here in Santa Fe, New Mexico, Eric Olson showed why he?s received a number of awards from the American Heart Association, and why one of his earlier papers, linking calcineurin to cardiac hypertrophy, was a Hot Paper in 2000.

The highlight of Olson?s talk was data on a HDAC7 ?- chromatin remodeling enzyme histone deacetylase 7 -- mouse knockout that died a massive cardiac death during embryonic development. The mice are fine until day 11, but by day 11.5, they?ve bled out, having suffered vascular dilatation, heart failure, and pericardial effusion. In the knockouts, smooth muscle cells are recruited to the vasculature, but they never become organized, the result of defects in endothelial cell adhesion that lead to a lack of tight junctions.

Olson?s group has replicated the findings in human umbilical vein endothelial cells treated with RNAi that targets HDAC7. In vitro, such cells normally form vascular structures, but after RNAi treatment, they don?t. Taking the work to the gene function level, the team found that matrix metalloproteinase 10 (MMP10) ? a member of a family of proteins involved in degradation of the extracellular matrix ? was upregulated 6.5-fold, while tissue inhibitors of MMPs, or TIMPs, were downregulated, suggesting one potential mechanism of action ? repression of MMP10 ? for HDAC7.

Many things remain unclear about the role of HDAC7, but its previous association with atherosclerosis, in which it is upregulated, and Olson?s dramatic knockout findings, generated a great deal of interest and questioning. The meeting will continue in Olson?s vein for a few days of talks and posters on molecular mechanisms of cardiac disease, and will then shift its focus to regeneration, which was the subject of Randall Moon?s talk that preceded Olson?s. It appears from looking at the agenda that in many cases, regeneration here means using stem cells to repair cardiomyocyte damage. Stay tuned for notes about Moon and other presentations.