More Ways to Connect
  LinkedIn Twitter YouTube Instagram
  RSS
Search
News

University of Cincinnati Academic Health Center
Publish Date: 03/07/03
Media Contact: AHC Public Relations, (513) 558-4553
print
PDF download
RSS feed
related news
share this
UC, Harvard Researchers Link PLN Protein Mutations to Heart Failure

Researchers at the University of Cincinnati and Harvard have newly published studies showing that mutations of the human PLN gene are linked to heart failure.  The UC research, led by Litsa Kranias, PhD, professor of pharmacology and cell biophysics, appears in the Feb. 26 edition of the Journal of Clinical Investigations. The Harvard group's findings appear in the Feb. 28 issue of Science.

"In recent years, naturally occurring genetic mutations have been associated with enlargement of the heart chambers in humans, but never before has there been documented proof that mutations in the PLN gene are linked to heart failure," said Dr. Kranias. The PLN gene is responsible for the presence of a critical calcium-regulating protein called phospholamban. Both studies identified, for the first time, naturally occurring mutations in the human gene for phospholamban, and show that such mutations in the PLN gene are linked to heart failure.  This link to a natural genetic mutation may help scientists develop new and better drug treatments for heart failure.

Heart failure is a condition characterized by impaired ability of the heart to supply adequate amounts of oxygen and nutrient-rich blood to the body, and is a major cause of death and disability.  Despite recent advances in therapy for other forms of heart disease, heart failure is the only cardiovascular disease increasing in incidence and prevalence, with nearly 500,000 new cases annually.  The prognosis for heart failure is worse than that for most cancers, with less than 50 percent of the patients surviving another five years. The only real  "cure" for heart failure at this time is a heart transplant. Unfortunately the opportunity for a heart transplant is severely limited by the availability of suitable donor hearts, and transplantation itself generates problems associated with organ rejection. "Identifying new forms of therapy for failing hearts is a medical priority," said Gerald Dorn, MD, professor and director of the Division of Cardiology in the UC College of Medicine. 

The first medical treatment for heart failure was digitalis obtained from the leaves of the foxglove plant. Digitalis continues to be the active ingredient in the medication known as digoxin and it is often used to treat heart failure today. Digitalis works by increasing the amount of available calcium to heart cells, permitting them to contract more efficiently. Impaired movement (storage and release) of calcium is now known to be always present in heart failure and cardiomyopathy (enlarged heart) in animals and humans.

Kranias and co-workers have shown that phospholamban is a critical regulator of calcium movement in heart cells and acts as a "brake" on the actions of calcium-cycling pumps in the heart.  When adrenaline is secreted during physical exertion or mental agitation, the phospholamban "brake" is released. This improves calcium-cycling, increases the contraction or pumping action of the heart, and is widely known as the "fight or flight" response.  

Improving cardiac function through inhibition of phospholamban has been proposed as a future treatment for heart failure. In fact, mice generated by the Kranias research team, where phospholamban has been entirely eliminated by disrupting its gene in "knock-out" mice or inhibited by expressing mutants with impaired activity as in "transgenic" mice, have strikingly  improved heart function.  "But what is true in mice is not necessarily true in man, and the effects of phospholamban inhibition or elimination in humans have not been previously described," Dr. Dorn said.

The phospholamban mutation identified by Dr. Kranias' team resulted in dramatically diminished phospholamban protein in the heart, much like that observed in the "knock-out" mouse model.  Surprisingly, and contrary to the expected benefits of phospholamban elimination in human hearts, individual mice carrying two copies of the mutant gene developed heart failure and died  at an early age, demonstrating an unexpected essential role for phospholamban activity in human hearts. 

The phospholamban mutation discovered by the Harvard researchers had the opposite biochemical effect, but the end result was the same. The impaired ability to "release the phospholamban brake," was also associated with onset of heart failure, in the form of a heart enlargement during the teenage years. As the heart enlarges, the valves don't fit snugly and leak (mixing the oxygen-rich blood with the oxygen-depleted blood). Studies of phospholamban activation in transgenic mice confirmed that phospholamban activation, and the resulting impairment of cardiac function, damages the heart's ability to contract and leads to heart failure.

"Taken together, these two experiments of nature, in which naturally occurring mutations of human phospholamban are associated with distinct disease processes, clearly demonstrate the critical role that either absence of, or unregulated activation of, this calcium-regulating protein can play in hereditary heart disease," said Dr. Dorn.

References for the scientific journals are:

February 26, 2003 Journal of Clinical Investigations:  Human Phospholamban Null Results in Lethal Dilated Cardiomyopathy Revealing a Critical Difference Between Mouse and Man
Kobra Haghighi, Fotis Kolokathis, Luke Pater, Roy A. Lynch, Michio Asahi, Anthony O. Gramolini, Guo-Chang Fan, Dimitris Tsiapras, Harvey S. Hahn, Stamatis Adamoupoulos, Stephen B. Liggett, Gerald W. Dorn II, David H. MacLennan, Dimitrios and Evangelia G. Kranias.


February 28, 2003 Science: Dilated Cardiomyopathy and Heart Failure Caused by a Mutation in Phospholamban
Joachim P. Schmitt, Mitsuhiro Kamisago, Michio Asahi, Guo Hua Li, Ferhaan Ahmad, Ulrike Mende, Evangelia G. Kranias, David H. MacLennan, J.G. Seidman, Christime E. Seidman.


 back to list | back to top