A rare case of familial heart failure has shown that a loss of calcium regulation in heart cells may directly cause this hereditary form of the disease. The researchers who studied the case, from the Harvard Medical School lab of Christine Seidman, professor of medicine, and Jonathan Seidman, the Bugher Foundation professor of genetics, developed transgenic mice for their work that now offer a model for further investigation of heart failure and calcium signaling. The study, led by research fellow Joachim Schmitt and published in the Feb. 28 Science, suggests a specific protein target for future heart disease therapies.
From the Harvard Medical School :
Mutant protein linked to heart failure
Protein would be prime target for new heart disease therapies
BOSTON, MA ? A rare case of familial heart failure has shown that a loss of calcium regulation in heart cells may directly cause this hereditary form of the disease. The researchers who studied the case, from the Harvard Medical School lab of Christine Seidman, professor of medicine, and Jonathan Seidman, the Bugher Foundation professor of genetics, developed transgenic mice for their work that now offer a model for further investigation of heart failure and calcium signaling. The study, led by research fellow Joachim Schmitt and published in the Feb. 28 Science, suggests a specific protein target for future heart disease therapies.
Current treatments for heart failure are non-specific, usually aimed at reducing the fluid buildup that occurs when the heart loses its ability to pump the blood. Christine Seidman says the question that should guide more targeted heart therapies is, “What are the fundamental signals that tip a diseased heart into a failing heart?” The recent findings contribute to the answer.
Calcium signaling, which enables the heart muscle to contract and relax, is known to be disrupted in heart failure. But it has been unclear whether the disturbance is a cause of failure or a downstream effect.
The contraction and relaxation of the heart is governed by a precise cycle of calcium intake and release. In cardiac muscle cells, calcium is tucked away inside reservoirs until an initial calcium signal through the cell’s membrane triggers its release. Calcium stores empty out, and the muscle contracts. The calcium is then forced back into these structures by a protein pump, SERCA2a, allowing the muscle to relax again. Phospholamban (PLN) is a small protein that regulates the SERCA2a pump.
The Seidman lab, in collaboration with David MacLennan, professor of medical research at the University of Toronto, examined a family in which several members develop heart failure by their mid-20s, a severe form of the disease that can often only be helped by heart transplantation. The team found that all the affected individuals in the family had a small mutation in the PLN gene.
To see what effects the mutation had on the protein’s function, the team developed a transgenic mouse model that expresses the mutant protein. These mice develop the dilated cardiomyopathy and rapidly progressing heart failure that mirrors the human disease.
Using human cultured cell lines, the team then determined how the mutation affects PLN’s normal role in calcium uptake. In its activated state, PLN inhibits the SERCA2a pump. PLN is deactivated when a molecule called protein kinase A adds phosphate groups to it, a chemical process that allows SERCA2a to function and the muscle cell to relax. The Seidman team found that the mutated form of PLN binds to protein kinase A and keeps it from phosphorylating and deactivating the normal form of PLN. With PLN constantly active, SERCA2a never has a chance to pump calcium back into the cell reservoirs, leading to contractile dysfunction of the heart. Christine Seidman is also in the Department of Medicine at Brigham and Women’s Hospital.
Because the mutated form of PLN interferes with the normal form, having one mutated copy of the gene is enough to cause disease. Most other genes that have been linked to heart failure are related to the structure of heart muscle cells and their ability to contract and relax. The current study suggests that in some cases, a failure to take calcium back into cell reservoirs is a primary cause of the disease. PLN is expressed almost exclusively in heart muscle, making it a specific target for potential therapies.
