(PHILADELPHIA) – In almost all forms of
heart failure, the heart begins to express genes that are normally
only expressed in the fetal heart. Researchers have known for years
that this fetal-gene reactivation happens, yet not what regulates
it. Now, investigators at the University of Pennsylvania
School of Medicine have discovered that an enzyme important
in fetal heart-cell development regulates the enlargement of heart
cells, known as cardiac
hypertrophy, which is a precursor to many
forms of congestive
heart failure (CHF).
The study, which paves the way for new targets for treating cardiac
hypertrophy and heart failure, appears this week in an advanced
online publication of Nature Medicine.
“It’s as if old programs are being reactivated in
a sick heart,” explains senior author Jonathan A.
Epstein, MD, the W.W. Smith Endowed Chair for Cardiovascular
Research at Penn. “In an adult heart, stresses such as high
blood pressure induce the reexpression of a fetal gene program.”
Expression of HDAC2 (red) in mouse fetal heart
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The investigators found that by inhibiting the enzyme HDAC in
adult mice the fetal-gene program can be prevented from restarting. “We
found that in various mouse models of cardiac hypertrophy and heart
failure, treatment with chemical HDAC inhibitors or genetic deletion of HDAC2 prevented the beginning of the downward slide
to progressive heart failure,” says Epstein.
HDAC is an enzyme switch that regulates how DNA is packaged inside
the cell, and therefore how large groups of related genes are turned
on and off. During development HDAC normally regulates proliferation of heart cells in the embryo. “This makes sense if a molecular
pathway in which HDAC has a major role is re-expressed--the adult
heart instead makes the cells it already has bigger since it is
unable to make more cells very easily.”
The researchers also found that HDAC works in the heart in part
by regulating expression of another enzyme called Inpp5f, which
is involved in a pathway that controls the growth and multiplication
of cells. Inpp5f is also related to tumor-suppressor
“HDAC and Inpp5f give us new targets for regulating cardiac
hypertrophy,” says Epstein. “Inhibitors of HDAC may
warrant testing for cardiac disease to stop the hypertrophy that
accompanies the re-expression of the fetal-gene program.”
HDAC inhibitors are already in trials for cancer and one, valproic
acid, has been used for years to treat seizures. Most CHF medications
are aimed at regulating blood pressure, but very few are targeted
at the heart-muscle cells themselves. About 5 million Americans
are living with CHF today, according to the American
“To understand how to better treat heart disease at the
cellular level is an important next step,” says Epstein.
This study was funded by the National
Institutes of Health.
Co-authors in addition to Epstein are Chinmay M. Trivedi, Yang
Luo, Zhan Yin, Maozhen Zhang, Wenting Zhu, Tao Wang, Thomas Floss,
Martin Goettlicher, Patricia Ruiz Noppinger, Wolfgang Wurst, Victor
A. Ferrari, Charles S. Abrams, and Peter J. Gruber.
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