Duke Researchers Genetically Engineer Mice To Block Heart Enlargement

April 23, 1998

DURHAM, N.C. - Researchers at Duke University Medical Center have genetically engineered mice to produce a protein that acts as a molecular decoy to stop enlargement of the heart -- a primary step to heart failure.

The decoy mimics a small portion of a protein called Gq, a molecular switch that causes heart cells to grow in response to high blood pressure. Flooding cells with non-working versions of Gq prevents the reception of molecular signals that normally would produce enlargement.

The research is the first to show definitively that Gq triggers enlargement of the heart, a common first step that leads to congestive heart failure, which kills 40,000 people a year in the United States.

The researchers -- who reported their research in the April 24 issue of the journal Science -- said their achievement raises the possibility that a single drug or genetic therapy could shut down the process that leads to enlarged heart in humans.

"We have shown in living animals that the final, common pathway to heart enlargement in response to pressure overload on the heart is through the protein Gq, which initiates the cascade of events inside the cell that lead to an enlarged heart," said Walter J. Koch, an assistant professor of experimental surgery, who led the team. "Our hope is that by demonstrating it is possible to block this initiation step, we will eventually be able to slow or prevent the steps that lead to heart failure in people."

Heart disease symptoms such as chronic high blood pressure and clogged coronary arteries put a strain on the heart. As it tries to compensate, the body produces hormones to force the heart to pump harder. This leads to an enlarged heart or myocardial hypertrophy. The heart gets bigger, it does not add any new muscle, and the existing muscle cells simply get larger. Although the additional muscle mass helps at first, over time the heart walls can harden and hamper rather than bolster the pumping action. This leads to congestive heart failure.

Congestive heart failure is notoriously difficult to treat, although early symptoms are often mild, and can be treated with changes in diet and exercise. As the disease progresses, less and less can be done. Traditional treatments for the early stages of heart failure include drug regimens consisting of multiple medications, such as beta blockers and ACE-inhibitors, to block the various hormones that produce a strain on the heart. If these drugs fail and the disease progresses, patients can receive a heart transplant as a last resort.

"Right now patients with hypertension are treated with several drugs that block the action of various hormones," said Koch. "Now that we have shown Gq is the final common pathway that signals pressure overload hypertrophy, we think it will be possible to design a single drug or gene therapy strategy to do the work that many separate types of drugs accomplish now. We believe such a strategy may be more efficient, since such a drug would target a specific molecule (Gq) instead of only one of a multitude of receptor signals, which is the case now."

The researchers, which also include Dr. Shahab Akhter, the paper's first author, Dr. Louis Luttrell, Dr. Guido Iaccarino, Dr. Robert Lefkowitz, a Howard Hughes Medical Institute investigator, all of Duke, and Dr. Howard Rockman of the University of North Carolina at Chapel Hill, hope to develop strategies to treat congestive heart failure in people using gene therapy, insertion of genes into heart cells to prevent or repair damaged heart muscle. The research was supported by grants from the National Institutes of Health, a National Research Service Award, and the North Carolina chapter of the American Heart Association.

The hormones angiotensin II, endothelin I, and the neurotransmitter norepinephrine regulate contraction and relaxation of arteries. When released in high doses, these hormones signal heart cells to grow by binding to receptors on the heart cell surface. Conventional methods of treating hypertension and preventing enlarged heart typically include using drugs to block these hormones such as from attaching to angiotensin II and alpha 1 adrenergic receptors on the surface of heart cells. Researchers knew that these hormones work at least in part by sending messages through their respective receptors on heart cells to the interior of the cell. There a protein called Gq acts like a relay station, receiving messages from many receptors and sending them on to the cell's nucleus, where they are translated into a message for the cell to grow larger.

Koch and his colleagues wanted to bypass the conventional method of inhibiting pressure overload enlargement by going straight to the Gq signaling protein. They studied the Gq protein and found a single segment that seemed to act like a receiver for all the various receptor messages. Koch and his research team then devised the "decoy" receiver, a small piece of a protein, also called a peptide, that mimicked the Gq receiver. Then they inserted a gene encoding the decoy into mouse embryos. The resulting transgenic mice made the decoy protein in their heart cells.

Then the researchers induced pressure overload, a mimic for high blood pressure in people, in the transgenic mice and in normal mice. The hearts of the mice with the decoy protein enlarged about 13 percent, compared to 40 percent in normal mice.

Koch and his colleagues next plan to study the effect of blocking Gq in arteries throughout the body, to see if their molecular decoy might be an effective anti-hypertension strategy, in addition to blocking enlargement of the heart.

Duke University Medical Center

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