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Heart Failure Prevented Through A Single Gene, UCSD Study Shows

Date:
November 1, 1999
Source:
University Of California, San Diego
Summary:
Cardiac researchers at the University of California, San Diego (UCSD) School of Medicine have demonstrated in mice that the progression of heart failure can be completely arrested by inhibiting a single gene called phospholamban (PLB). This gene is one of a family of calcium-cycling genes whose function is to regulate the movement of calcium within heart muscle cells.
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Cardiac researchers at the University of California, San Diego (UCSD) School of Medicine have demonstrated in mice that the progression of heart failure can be completely arrested by inhibiting a single gene called phospholamban (PLB). This gene is one of a family of calcium-cycling genes whose function is to regulate the movement of calcium within heart muscle cells. Calcium activates cardiac contraction.

This work appears in the October 29 issue of the journal Cell.

Normally, PLB acts as a brake on the calcium pump, which is responsible for increasing calcium into storage sites so that it can be released with each heartbeat. Hormones that increase heart rate and function, such as adrenaline, release the brake. This balance between accelerator and brake is disrupted in heart failure. In that setting, because of injury such as a heart attack or a genetic defect, the brake is on too hard, thus calcium is restricted and heart function weakens.

To assess the role of calcium-cycling defects in heart failure, Kenneth Chien, M.D., Ph.D., and colleagues cross-bred a mouse that is genetically engineered to develop heart failure (called MLPKO*) with a mouse that lacks PLB. The offspring exhibited no signs of heart failure.

"We have developed a double-knockout mouse that, by all measures, rescues itself from heart failure," said Chien, UCSD professor of medicine and director of the UCSD-Salk Program in Molecular Medicine, a joint program to train the next generation of leading physician-scientists.

Then, to directly test if the inhibition (or lack) of PLB was responsible for preventing heart failure, the researchers engineered specific mutations in PLB that interfered with its ability to interact with the calcium pump. A viral vector was then used to deliver the mutant PLB gene into normal and MLPKO mouse heart-muscle cells.

"We've designed a mutant gene that inhibits its normal counterpart. In essence, it inhibits itself," said Chien. "This variant gene is a potential therapeutic agent, and opens the door for gene therapy for heart failure."

A more immediate application may come in the form of development of drugs targeted at inhibiting PLB. Current medical treatment for heart failure includes administering catecholamine drugs, such as adrenaline or epinephrine, to increase the heart's pumping strength. These drugs help with symptoms of the disease somewhat; however, they have damaging long-term side effects, primarily triggering abnormal heart rhythm and increasing the risk of sudden death. PLB is found only in muscle cells and is the last critical switch in the adrenaline pathway for increasing heart function. Thus, the new inhibitor drugs likely would have few side effects. Mice that have lost the PLB gene display no obvious side effects and survive to a normal lifespan.

Heart failure is the number one cause of hospital admission in the U.S. and in many developed nations. This chronic and debilitating disease affects the lives of 3.5 million Americans. It is the only cardiovascular disease increasing in frequency and incidence.

"Ironically, heart failure is increasing as a result of our success in treating other heart problems such as heart attacks," said Chien, who is a cardiologist and molecular biologist. "Advances in cardiac care are resulting in more people surviving heart attacks, but damage to the heart muscle from the attack places patients at high risk for developing heart failure."

While this research has shown that inhibiting PLB stops progression of heart failure, the researchers next want to test if heart failure can be reversed through PLB inhibition. Also, there are many types of heart failure. The current paper reports prevention of heart failure that results from a genetic mutation. Chien and colleagues want to test inhibition of PLB, or other calcium-cycling genes, in heart failure that results following a heart attack.

Co-authors on the paper are (from UCSD School of Medicine) Susumu Minamisawa, Masahiko Hoshijima, Yusu Gu, Maryann E. Martone, Yibin Wang (now of University of Maryland School of Medicine), and John Ross Jr.; (from University of Cincinnati College of Medicine) Guoxiang Chu, Konrad Frank and Evangelia G. Kranias; (from University of Calgary School of Medicine) Christopher A. Ward (now of Queen's University Kingston, Ontario, Canada) and Wayne R. Giles.

This research was funded through grants from the National Institutes of Health.

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* The MLPKO was the first reported mouse model of dilated cardiomyopathy and was characterized in 1997 in the Chien lab.


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The above story is based on materials provided by University Of California, San Diego. Note: Materials may be edited for content and length.


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University Of California, San Diego. "Heart Failure Prevented Through A Single Gene, UCSD Study Shows." ScienceDaily. ScienceDaily, 1 November 1999. <www.sciencedaily.com/releases/1999/11/991101075811.htm>.
University Of California, San Diego. (1999, November 1). Heart Failure Prevented Through A Single Gene, UCSD Study Shows. ScienceDaily. Retrieved May 24, 2015 from www.sciencedaily.com/releases/1999/11/991101075811.htm
University Of California, San Diego. "Heart Failure Prevented Through A Single Gene, UCSD Study Shows." ScienceDaily. www.sciencedaily.com/releases/1999/11/991101075811.htm (accessed May 24, 2015).

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