- 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 Philadelphia.
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
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Related links:
http://www.chop.edu
CONTACT:
John Ascenzi of The Children's Hospital of
Philadelphia, +1-267-426-6055, Ascenzi@email.chop.edu
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