Oct. 3, 2003 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 bleeding.
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 entire body."
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 of Health.
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