(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
Click on thumbnail
to view full-size image
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.
PENN Medicine is a $2.9 billion enterprise
dedicated to the related missions of medical education, biomedical
research, and high-quality patient care. PENN Medicine consists
of the University of Pennsylvania School of Medicine (founded in
1765 as the nation's first medical school) and the University of
Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt
of NIH research funds; and ranked #3 in the nation in U.S. News
& World Report's most recent ranking of top research-oriented
medical schools. Supporting 1,400 fulltime faculty and 700 students,
the School of Medicine is recognized worldwide for its superior
education and training of the next generation of physician-scientists
and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals,
all of which have received numerous national patient-care honors [Hospital
of the University of Pennsylvania; Pennsylvania Hospital, the nation's
first hospital; and Penn Presbyterian Medical Center]; a faculty practice
plan; a primary-care provider network; two multispecialty satellite
facilities; and home care and hospice.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.