Cells have molecule for protein triage

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  • Radiation therapy keeps arteries clear Each year, about 500,000 people in the

    United States have their clogged heart ar- teries cleared by angioplasty. In the costly, sometimes risky procedure, a surgeon re- opens the artery by inserting, inflating, and then removing a tiny balloon. But for about half the patients, the treated artery reclogs within 6 months.

    Two new studies add to a growing body of evidence that radiation applied within an artery might reduce that recurrence rate.

    Recently, surgeons have been insert- ing stents, or metal mesh cylinders, into arteries after angioplasty to hold them open longer. However, the stents dont always avoid the problem of repeat clogging, or restenosis, caused by the buildup of scar tissue from injury dur- ing angioplasty.

    Earlier studies suggested that among patients with stents, those exposed briefly to a localized dose of radiation are signifi- cantly less likely to have the stent become clogged than are patients who received no radiation (SN 6/14/97, p. 364).

    In one of the new studies, the largest of its kind, researchers treated 252 patients who had clogged stents. All had chest pain and impaired blood flow to their heart-two conditions resulting from blocked arteries.

    Clinicians replaced the stents or cleared

    the stent area by angioplasty or with a tis- sue-removing tool. They then placed a string of iridium-I92 pellets inside the treated arteries of roughly half the pa- tients for up to 20 minutes. Iridium-192 emits gamma rays, which thwart the scar- ring process. The rest of the patients, the studys control group, received a similar but nonradioactive string.

    As expected, arteries closed back up within 6 months in 51 percent of the con- trol group. But only 22 percent of patients who received radiation experienced a relapse, says study coauthor Paul S. Teirstein, a cardiologist at the Scripps Clin- ic and Research Foundation in La Jolla, Calif. He and his colleagues report the findings in the Jan.25 NEW ENGLAND JOURNAL OF MEDICINE (NEJM).

    Theres a catch. One of the side effects of the radiation, the investigators found, was an increase in blood clots, which can cause heart attacks. Replacing a stent also may lead to blood clots.

    But we think weve solved that prob- lem, says study leader Martin B. Leon, a cardiologist at Lenox Hill Hospital in New York. He says that doing fewer stent re- placements and treating patients with an- ticlotting drugs for 8 weeks after radiation can bring the risk of clot formation down to that of the control group.

    In a related study also published in the

    Cells produce bad proteins all the time, and in largeenough numbers, these mole cules can spell danger for the body. When misfolded or unfolded, proteins cant do their jobs. At worst, they harm cells by clumping into the sticky plaques that are the signatures for neurodegenerative dis- orders such as Alzheimers disease.

    A clear understanding of how most cells successfully manage protein repair and disposal has been elusive. But now, research has unmasked one of the mo- lecular participants in the process. In the January NATURE CELL BIOLOGY, scientists studying gene expression in failing hearts report the function of an impor- tant molecular player in the cells quality- control system.

    Called CHIP (carboxyl terminus of Hsc70-interacting protein), this molecule decides the fate of malformed proteins in heart muscle, says Cam Patterson of the University of North Carolina at Chapel Hill. CHIP judges whether to slate bad proteins for repair or destruction, he says.

    The findings may help researchers piece together the puzzle of protein regu- lation and lead to a new generation of therapies for heart disease and nervous system disorders, says Patterson.

    Cells have molecule for protein triage The process of protein sorting has

    been dubbed triage for its similarity to the way that medical personnel sort pa- tients in emergency rooms. Proteins ex- ist in the cell in three different states: functional, misfolded or unfolded but salvageable, and beyond all hope.

    During protein triage, the refolding molecules, called chaperones, recognize misfolded peptides and tidy them up (SN: 9/6/97, p. 155). Another cellular molecule, a proteasome, breaks apart those protein candidates that are be- yond fixing. Until now, however, theres been no direct link between the mole- cules charged with fixing the folding and those that destroy proteins.

    Hearts under stress are loaded with both damaged proteins and molecules that refold proteins. Patterson and his colleagues discovered that CHIPS abun- dance in the heart also increases during stress. The group then suspected that CHIP is the triage arbiter.

    During triage, CHIP steps in and binds to a chaperone thats holding a badly misshapen protein, preventing any re- folding, the team reports. Instead, CHIP shuttles the reject to the proteasome, which destroys it.

    Whats interesting about [CHIP] is it

    54 SCIENCE NEWS, VOL. 159

    Jan. 25 NEJM, surgeons in Europe per- formed first-time angioplasty on 181 pa- tients. Immediately after the procedure, researchers randomly assigned patients to receive one of four different doses of ra- dioactive yttrium-90-which emits beta rays-within their arteries. Surgeons de- livered the radiation from a small wire in- side a catheter. They removed the appara- tus after 2 to 3 minutes.

    After 6 months, the relapse rates in the groups ranged from 4 to 28 percent ac- cording to radiation dose-the more the radiation, the fewer patients relapsed.

    The study shows that it is possible, with the use of [beta radiation], to . . . mimic the natural defense mechanisms against atherosclerosis, or the process of arterial clogging, says study coauthor William Wijns, a cardiologist at the Cardio- vascular Center, OLV Hospital in Aalst, Belgium.

    Although the results of the two new studies seem promising, says Mark J. Eisenberg, a cardiologist at the Jewish General Hospital in Montreal, the use of ra- diation against restenosis is really in its infancy. He notes that data from these and previous studies have been limited to a year or less of follow-up.

    Theres a danger in widespread dis- semination of a technology before its long- term effects are known, he cautions. For a potentially dangerous technology, we would like to have at least 5 years of fol- low-up. -L. Wang

    seems to have two different functional units that are linked together, says Ju- dith Frydman, who studies protein fold- ing at Stanford University. One unit binds CHIP to a chaperone, and the other pres- ents the protein to the proteasome.

    CHIP, Patterson asserts, represents a major pathway for degrading spoiled pro- tein and keeping the cell on track making good protein. The balance seems to be a yin-yang situation, he says. We have known more about the yin-when to re- fold proteins. Now, were trying to learn about the yang-understanding when they are discarded and why.

    We have thought that the cells would have a powerful means for clearing out [hopelessly damaged proteins], a cellu- lar garbage can, says Patterson. He and his colleagues suggest that a chemical resembling CHIP could be used as a drug to clear away damaged proteins in the heart and other organs.

    I think this is really an exciting paper because for the First time it links. . . pro- tein folding and protein degradation, says Marschall Runge, a cardiovascular researcher also at the University of North Carolina. These two areas are criti- cal during a heart attack, and a better un- derstanding of their linkage will open up a new area for development of therapeu- tic strategies, he says. 4. Netting

    JANUARY 27,2001

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