| October 1, 2003
When Heme Attacks: After Trauma,
The Molecule that Makes Life Possible Rampages
PENN Researchers Find How Heme Harms - And How To
Prevent The Damage
(Philadelphia, PA) - Heme, the iron-bearing,
oxygen-carrying core of hemoglobin, makes it possible
for blood to carry oxygen, but researchers from the
University of Pennsylvania School of Medicine
have determined how free-floating heme can also make
traumatic events worse by damaging tissue. The Penn
researchers present their findings in the October 2nd
issue of the journal Nature. Fortunately, the
researchers also identified a chemical that can be targeted
by drug developers to impede the deleterious effects
of free-floating heme.
Following a traumatic event - such as an accident,
a stroke, a heart attack or even surgery - heme floods
the spaces between and inside cells and exacerbates
the damage. It does so by shutting down an important
cell membrane channel, an action that kills neurons
and constricts blood vessels. While investigating this
process, the researchers also determined that a chemical
called NS1619 restores the function of the cell membrane
channel. NS1619 and its derivatives could be the source
for a new drug - one that prevents the secondary events
that worsen trauma damage.
"Following a heart attack, a stroke, or any really
severe physical injury, heme is literally shaken loose
from hemoglobin," said Xiang Dong Tang, MD, PhD,
Staff Scientist in Penn's Department of Physiology.
"Normally, cells can compensate and recycle loose heme.
But when larger concentrations are released, heme can
gum up the works, specifically the Maxi-K ion channel,
a cell membrane protein important for blood vessel relaxation
and neuron excitability."
Maxi-K is a channel that moves potassium ions out of
cells. In the Nature paper, Tang and his colleagues
prove that the Maxi-K protein possesses sites that bind
heme. If these sites were removed or altered, heme could
not effect Maxi-K proteins. "Maxi-K is found in the
lining of blood vessels. When it is turned off, the
vessel constricts, increasing blood pressure, which
is decidedly not beneficial following a heart attack,
" said Toshinori Hoshi, PhD, Associate Professor
in Penn's Department of Physiology and co-author of
the Nature article. "In neurons, disrupting Maxi-K
leads to excessive calcium accumulation. Eventually,
this ionic buildup triggers cell suicide and, therefore,
the loss of the neuron."
The chemical heme is essential for most forms of life.
It exists in hemoglobin for oxygen transport, in cytochromes
for cellular energy production, and in guanylate cyclase
for blood pressure regulation. The molecule itself is
tiny, a flat snowflake of a carbon framework surrounding
a single atom of iron, but it is crucial for the cellular
process of respiration and the action of nirtroglycerine.
"Generally, the heme molecule is attached to larger
molecules, such as hemoglobin, but it is easily set
loose. Indeed, there is an entire cellular industry
behind recycling and reusing 'lost' heme," said Tang.
"But that system can get overwhelmed in times of serious
trauma and bleeding."
Studying the heme recycling system might prove useful
in developing treatments for preventing the secondary
damage set off by heme. Certain cells, such as neurons,
do have ways of transporting heme. If the 'heme transport'
is identified and the specific blocker is found, it
could help prevent symptoms resulting from trauma and
Meanwhile, according to Tang and his colleagues, there
is already a known agent that can relieve Maxi-K from
heme inhibition. NS1619 is known as the "Maxi-K opener,"
and, as the researchers have shown, readily reverses
the heme-mediated inhibition.
"I can envision the use of a drug similar to NS1619
as an emergency treatment," said Tang. "In the emergency
room, after an accident or heart attack, it could be
used to keep the damage from continuing on a cellular
level - before it could result in bad effects for the
Scientists also contributing to this research include
Rong Xu from Penn, Mark F. Reynolds, from St. Joseph's
University, Marcia L. Garcia, from Merck Research Laboratories,
and Stefan H. Heinemann, from Friedrich Schiller University.
Funding for this research came from the National Institutes
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