Novel Approach May Protect Against Heart Attack Injury
- Drugs Target Gene Pathways to Preserve Heart, Possibly Other Organs -
PHILADELPHIA, July 10 /PRNewswire-USNewswire/ -- Researchers at
The Children's Hospital of Philadelphia have manipulated cell
activity that occurs during the interruption of blood flow to
strongly protect heart tissue in animal studies. The finding has
the potential to become an emergency treatment for heart attack
patients, particularly since already existing drugs might be
pressed into service to produce the protective effects.
"Reduced blood flow, or ischemia, is a major problem in many
organs, where it can lead to cell death and tissue damage," said
study leader Peter J. Gruber, M.D., Ph.D., a cardiothoracic surgeon
at Children's Hospital and a faculty member of the University of
Pennsylvania School of Medicine. "We decided to look for a global
approach to protecting heart tissue by inhibiting enzymes that
govern how cells respond to ischemia."
Gruber's team published their findings online July 7 in the
journal of the Federation of American Societies for Experimental
Biology (FASEB). The article will appear in the journal's October
2008 print issue.
The researchers made use of drugs called histone deactylase
(HDAC) inhibitors that alter the way DNA is packaged within cells,
as well as modifying the function of other proteins. Building on
previous work by other researchers, who showed that HDAC inhibitors
reduce ischemic injury in the brain, they used the same agents in
mice with induced heart damage.
"We found significant and dramatic results in the mice," said
Gruber. "The HDAC inhibitors reduced the area of tissue injury,
even when delivered an hour after the ischemic event occurred." The
size of the myocardial infarction--an area of dead tissue caused by
obstructed blood flow, as occurs after a heart attack--was reduced
by more than half.
In further investigating how the HDAC inhibitors acted, Gruber's
team found they blocked gene pathways that led to cell death and
ischemia-induced vascular permeability, the leakage of fluid
through blood vessels. They also identified a specific molecule,
HDAC4, as the likely HDAC enzyme with the most critical role in
affecting how cells respond to ischemia.
An important advantage of their finding, said Gruber, is that a
number of HDAC inhibitors are already used in medicine, for
treating both cancer and epilepsy, and are well-tolerated. Although
much research remains to be done, he added, this raises the
possibility that existing drugs, or modified versions of them,
might play an important new role in heart disease.
Because the protective effect of HDAC inhibitors may occur even
after the initial blockage of blood flow, therapies based on
Gruber's research may lead to an emergency treatment following a
heart attack. In addition, because open-heart surgery for both
children and adults requires a period in which the heart is
stopped, such treatment might also protect tissues from the adverse
effects of interrupting blood flow during surgery.
For now, said Gruber, the next step for his study team will be
to test how HDAC inhibitors work in protecting against ischemic
injury in larger animals.
A National Institutes of Health grant partially supported the
research, in addition to funding from the McCabe Foundation, the
University Research Foundation and the Division of Pediatric
Cardiothoracic Surgery at The Children's Hospital of
Gruber's co-authors were Anne Granger, Ibrahim Abdullah, Faith
Huebner, and Thomas Huebner, of Children's Hospital; and Jonathan
A. Epstein, M.D., of the University of Pennsylvania School of
Medicine. Gruber, Granger, and co-authors Andrea Stout and Tao Wang
are members of the Penn Cardiovascular Institute, of which Epstein
is the scientific director.
About The Children's Hospital of Philadelphia: The Children's
Hospital of Philadelphia was founded in 1855 as the nation's first
pediatric hospital. Through its long-standing commitment to
providing exceptional patient care, training new generations of
pediatric healthcare professionals and pioneering major research
initiatives, Children's Hospital has fostered many discoveries that
have benefited children worldwide. Its pediatric research program
is among the largest in the country, ranking third in National
Institutes of Health funding. In addition, its unique
family-centered care and public service programs have brought the
430-bed hospital recognition as a leading advocate for children and
adolescents. For more information, visit http://www.chop.edu/.
Contact: John Ascenzi Phone: (267) 426-6055 Ascenzi@email.chop.edu
Source: The Children's Hospital of Philadelphia
CONTACT: John Ascenzi of The Children's Hospital of
Web Site: http://www.chop.edu/
Posted: July 2008