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RESEARCH BRIEFSPeptide Promotes Angiogenesis Through Oxygen-restoring ProteinMaking further advances toward therapy to promote new blood vessel growth, researchers at the Beth Israel Deaconess Medical Center report in the January Nature Medicine the discovery of potent angiogenesis activity in a naturally occurring peptide, PR39. Produced by macrophages during an inflammatory response, the peptide's function has been largely unknown. PR39 apparently induces angiogenesis by elevating the levels of hypoxia-inducible factor-1 alpha (HIF-1 alpha), a protein known to act as a master regulatory switch when oxygen supplies to tissues become limited. Among the genes HIF-1 alpha regulates to restore oxygen are those that promote new blood vessel growth. The team found that PR39 increased HIF-1 alpha by preventing its degradation by the well-known ubiquitin–proteasome pathway. Angiogenesis was promoted by PR39 both in vitro and in vivo. In transgenic mice specifically expressing PR39 in the heart, vasculature was significantly increased (see figure). Encouragingly, expression of the gene was apparently nontoxic since there were no observable heart abnormalities. Jian Li, instructor in medicine; Youhe Gao, postdoctoral fellow; Michael Simons, associate professor of medicine; and colleagues believe they may have uncovered a key biological pathway explaining how tissue injury and angiogenesis are linked. Wound healing is known to be associated with new blood vessel growth, and scientists have longed to tap into the mechanism in order to develop therapies to promote angiogenesis in people with blocked coronary arteries and other vascular disorders.
Blood vessel growth is increased in the hearts of transgenic mice expressing PR39, as shown by enhanced CD31 expression (brown), an endothelial cell marker. (Muscle cell nuclei are stained blue.)
Air Pollution May Exacerbate Heart ProblemsResearchers at HSPH have found an association between air pollution and potentially life-threatening arrhythmias in people with a history of abnormal heart rhythms. The study builds on previous epidemiologic findings linking elevated air pollutants with cardiovascular-related hospital admissions and mortality. Some studies in animals also have shown detrimental effects of air pollutants on the heart. The population studied consisted of individuals with a history of serious arrhythmia who required implanted cardioverter defibrillators (ICDs). ICDs can detect sudden heart irregularities and save the patient's life by restoring normal cardiac rhythm. The device provides a record of arrhythmic events, along with the time they occurred. Douglas Dockery, HSPH professor of environmental epidemiology and HMS associate professor of medicine (epidemiology), the study's leader, and coworkers hypothesized that the incidence of arrhythmias recorded on ICDs would be higher during times when air pollutants were elevated. Indeed, they found statistically significant associations between arrhythmic events and atmospheric increases in nitrogen dioxide, carbon monoxide, black carbon, and fine particles. The effects on the heart did not follow exposures immediately, but instead occurred one to two days later. Speculating on the mechanism, the researchers believe that air pollutants may elicit an inflammatory response, resulting in autonomic nervous system activation and altered heart cell excitability. The researchers acknowledge some limitations in their study. For example, air samples were taken in Boston, but the participants lived throughout eastern Massachusetts. As the researchers point out, however, any misclassification of air samples showing that the air had somewhat more pollutants than the participants were exposed to would tend to bias the study toward less of a link. The study is published in the January Epidemiology. Editorial Says Think Twice About Hormone Replacement TherapyCommenting on a study in the Jan. 26 Journal of the American Medical Association, a group of HSPH faculty members says it is time to reevaluate whether the risks of hormone replacement in menopausal women outweigh the benefits. The study links long-term use of combined estrogen–progestin therapy with a greater risk of breast cancer. In their editorial in the same issue, authors Walter Willett, professor of epidemiology and nutrition and chair of the Nutrition Department; Graham Colditz, professor of epidemiology; and Meir Stampfer, professor of epidemiology and nutrition, say the study is in general agreement with previous work and raises concerns about the combined therapy. Estrogen and progestin together have become a standard hormonal regimen for women both during and after menopause. Estrogen alone, although beneficial in reducing osteoporotic fractures and coronary heart disease risk, has been associated with an increased risk of endometrial and breast cancers. Addition of progestin seems to reduce endometrial cancer risk, although the effect on breast cancer has been controversial. Willett and his colleagues acknowledge that while the latest study greatly strengthens the evidence in favor of risk, the association has not been definitively proven. Also, they say that cancer risk is determined by the duration of hormone therapy, and that short-term use—two or three years—for relief of menopausal symptoms should not be influenced by the fear of risks. The authors urge women and their physicians to consider whether long-term hormone replacement therapy is warranted. They do not believe that reduced risks of fractures and coronary heart disease provide sufficient justification, stating that avoidance of smoking, regular exercise, and a good diet are effective preventive measures. They point out that other drugs, some already available and others being developed, might provide additional options. These include selective estrogen receptor modulators such as raloxifene (Evista) and tamoxifen (Nolvadex). Though the goal of these drugs is to prevent osteoporosis while reducing the risk of breast and endometrial cancers, their long-term effects are unknown. In view of the uncertainties of hormone use, the authors believe the emphasis on these therapies and de-emphasis of other preventive measures needs to be reassessed. They say, "The commonly held belief that aging routinely requires pharmacological management has unfortunately led to neglect of diet and lifestyles as the primary means to achieve healthy aging." —Briefs by Lorene Leiter |
