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Study helps explain origins of cardiac fibrosis in patients with heart disease
July 30, 2007BOSTON -- A report led by researchers at Beth Israel Deaconess Medical Center (BIDMC) helps explain the origins of cardiac fibrosis, a stiffening of the heart muscle that leads to a variety of cardiac diseases, most notably heart failure.
The animal study, which appears today in the Advance Online Publication of Nature Medicine, also demonstrates that a bone morphogenic molecule known as rhBMP7 can reverse the cardiac fibrosis process, offering the possibility of a therapeutic target for this debilitating condition.
"Heart disease is the number-one cause of death in the Western world," explains the study's lead author Elisabeth Zeisberg, MD, a scientist in the Division of Matrix Biology at BIDMC and an Instructor of Medicine at Harvard Medical School (HMS). "And most people who suffer from heart disease have developed scarring of the heart tissue, known as fibrosis."
Fibrosis develops when the body's natural wound-healing process goes awry. Under normal conditions, specialized cells known as fibroblasts deposit layers of collagen protein to form a scar and thereby enable wounds to heal. However, in abnormal circumstances - and for unknown reasons - excessive production of matrix proteins, such as collagen, results in pathological scarring, or fibrosis. In the heart, the buildup of matrix leaves the organ stiff and inflexible, unable to properly relax and function.
"Fibrosis can develop in any organ in the body," explains Zeisberg. "While it's known that fibroblast cells are responsible for cardiac fibrosis, the source of these fibroblasts has remained unknown until now."
Zeisberg and senior author Raghu Kalluri, PhD, Chief of the Division of Matrix Biology at BIDMC, speculated that a specialized form of epithelial-mesenchymal transition (EMT) known as endothelial-mesenchymal transition might be the mechanism behind this turn-of-events.
"Our laboratory has had a longstanding interest in the area of organ fibrosis and the origin of fibroblasts in this setting," explains Kalluri, who is also Associate Professor of Medicine at HMS. "We have previously demonstrated that in the kidney, liver and the lung, epithelial cells under stress can convert into fibroblasts via epithelial-mesenchymal transition."
So, using knockout mice in which endothelial cells had been marked genetically, the investigators confirmed that during cardiac fibrosis, these cells were indeed converting into activated fibroblasts, which were depositing scar material and impeding the proper function and electrical conduction of the heart.
In the second part of the study, the investigators turned to the rhBMP7 protein to determine if it could successfully reverse the EndMT process and thereby reduce the development of fibroblasts and lead to the improvement of heart function.
"The rhBMP-7 protein was quite impressive in its ability to recover the function of damaged hearts," says Kalluri. "These findings provide compelling proof that the process of fibrosis can be reversed in the heart and offers the possibility of new therapies for patients who have developed cardiac fibrosis as the result of myocardial infarction, hypertension, valvular diseases or heart transplantation."
Beth Israel Deaconess Medical Center
Fibrosis develops when the body's natural wound-healing process goes awry. Under normal conditions, specialized cells known as fibroblasts deposit layers of collagen protein to form a scar and thereby enable wounds to heal. However, in abnormal circumstances - and for unknown reasons - excessive production of matrix proteins, such as collagen, results in pathological scarring, or fibrosis. In the heart, the buildup of matrix leaves the organ stiff and inflexible, unable to properly relax and function.
"Fibrosis can develop in any organ in the body," explains Zeisberg. "While it's known that fibroblast cells are responsible for cardiac fibrosis, the source of these fibroblasts has remained unknown until now."
Zeisberg and senior author Raghu Kalluri, PhD, Chief of the Division of Matrix Biology at BIDMC, speculated that a specialized form of epithelial-mesenchymal transition (EMT) known as endothelial-mesenchymal transition might be the mechanism behind this turn-of-events.
"Our laboratory has had a longstanding interest in the area of organ fibrosis and the origin of fibroblasts in this setting," explains Kalluri, who is also Associate Professor of Medicine at HMS. "We have previously demonstrated that in the kidney, liver and the lung, epithelial cells under stress can convert into fibroblasts via epithelial-mesenchymal transition."
So, using knockout mice in which endothelial cells had been marked genetically, the investigators confirmed that during cardiac fibrosis, these cells were indeed converting into activated fibroblasts, which were depositing scar material and impeding the proper function and electrical conduction of the heart.
In the second part of the study, the investigators turned to the rhBMP7 protein to determine if it could successfully reverse the EndMT process and thereby reduce the development of fibroblasts and lead to the improvement of heart function.
"The rhBMP-7 protein was quite impressive in its ability to recover the function of damaged hearts," says Kalluri. "These findings provide compelling proof that the process of fibrosis can be reversed in the heart and offers the possibility of new therapies for patients who have developed cardiac fibrosis as the result of myocardial infarction, hypertension, valvular diseases or heart transplantation."
Beth Israel Deaconess Medical Center
Scientists identify novel way to prevent cardiac fibrosis
In a study that points to a new strategy for preventing or possibly reversing fibrosis - the scarring that can lead to organ and tissue damage - researchers at the University of California, San Diego School of Medicine have determined that a molecule called Epac (Exchange protein activated by cAMP1), plays a key role in integrating the body's pro- and anti-fibrotic response.
Rice breakthrough could prevent multiple fibrotic diseases
A scientific breakthrough at Rice University could lead to the first treatment that prevents the build-up of deadly scar tissue in a broad class of diseases that account for an estimated 45 percent of U.S. deaths each year.
Aspirin might prevent Vioxx cardiac damage
Low-dose aspirin might prevent the cardiovascular damage known to arise from use of the painkiller rofecoxib (Vioxx®), suggest new findings from mouse studies by Duke University Medical Center researchers.
New technique for detecting cardiac fibrosis
A medical team of the Basque Country has discovered a new technique to detect cardiac fibrosis. After a research carried out during several years, it has been discovered that serum leves of PIP peptide is an indicator of increased myocardial fibrosis. Fibrosis is formed when scar tissue is accumulated in heart. As a consequence it causes stiffening of the heart and often heart failure. In order to fight against such disease, researchers started looking for an indicator substance in blood. Collagen amount and PIP This research started 10 years ago with spontaneoulsy hypertensive rats. As a result, they could find out that hypertensive disease increases the amount of heart collagen. On the
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