Blocking a key protein involved in calcium regulation can improve the function of failing heart cells, according to a study in the February 26 issue of Circulation. The work holds promise for treating congestive heart failure.
"We set out to inhibit a protein that blocks normal calcium flow in the heart," says principal investigator Roger Hajjar, MD, of the Cardiovascular Research Center (CVRC) and Heart Failure Center at Massachusetts General Hospital (MGH). "Usually with gene therapy, you add things, but here the strategy was to take something away."
Hajjar says heart failure in the aging is due to abnormal calcium levels in heart muscle cells. The current study focuses on phospholamban, a protein that regulates the activity of a molecular pump that controls calcium flow within cells and may be reduced in failing hearts. By blocking normal calcium regulation in heart cells, the natural inhibitory actions of phospholamban in a failing heart may prevent the cardiac muscle from relaxing and the heart from filling with blood appropriately. "When we targeted phospholamban, we were able to diminish it, and then calcium movement in the cells became normal," says Hajjar.
For the study, first author Frederica del Monte, MD, PhD, took cells from the hearts of nine end-stage patients who were about to undergo heart transplantations, with a goal of seeing if they could improve contraction and relaxation in these diseased cells using a gene therapy approach called antisense strategy. By injecting into cultured cell single-strand DNA that binds to the RNA message encoded by the phospholamban genes, the researchers were able to prevent the formation of the phospholamban protein. "When we knocked down the amount of protein that was formed, the heart cell contractions became normal," says Hajjar.
Ultimately, del Monte and Hajjar hope the treatment strategy can be used to correct heart failure and cut down on the need for heart transplants. "Over the past year, five patients at MGH alone have died while waiting for cardiac transplants," says Hajjar. "And for every cardiac transplant that is performed, there are so many patients on the waiting lists that die." He notes that many patients cannot even get on the waiting lists. Currently, preclinical trials are underway to test Hajjar?s antisense strategy in live animals.
Other co-authors of the report are G. William Dec, MD, of the MGH; Sian E. Harding, PhD, of the National (British) Heart and Lung Institute and Imperial College, London; and Judith K. Gwathmey, VMD, PhD, of Harvard Medical School. The study was supported by grants from the National Institutes of Health, the British Heart Foundation, and the Doris Duke Charitable Foundation.
The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $300 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photomedicine. In 1994, the MGH joined with Brigham and Women's Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.
Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.
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