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Key heart-failure culprit discovered

13.03.2014

Collaborative research study by Sanford-Burnham, Icahn School of Medicine at Mount Sinai, and UC San Diego shows blocking microRNA miR-25 halts progression of heart failure, improves cardiac function, and may increase survival


This is Sanford-Burnham's Mark Mercola, Ph.S.

Credit: Sanford-Burnham Medical Research Institute

 A team of cardiovascular researchers from Sanford-Burnham Medical Research Institute (Sanford-Burnham), the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai, and the University of California, San Diego have identified a small but powerful new player in the onset and progression of heart failure. Their findings, published in the journal Nature on March 12, also show how they successfully blocked the newly discovered culprit to halt the debilitating and chronic life-threatening condition in its tracks.

In the study, investigators identified a tiny piece of RNA called miR-25 that blocks a gene known as SERCA2a, which regulates the flow of calcium in and out of heart-muscle cells. Decreased SERCA2a activity is one of the main causes of poor contraction of the heart and enlargement of heart-muscle cells leading to heart failure.

Using a functional screening system developed by researchers at Sanford-Burnham, the research team discovered miR-25 acts pathologically in patients suffering from heart failure, delaying proper calcium uptake in heart-muscle cells.

"Before the availability of high-throughput functional screening, our chance of teasing apart complex biological processes involved in disease progression like heart failure was like finding a needle in a haystack," said study co-senior author Mark Mercola, Ph.D., professor in the Development, Aging, and Regeneration Program at Sanford-Burnham and professor of bioengineering at UC San Diego Jacobs School of Engineering. "The results of this study validate our approach to identifying microRNAs as potential therapeutic targets with significant clinical value."

Mercola's laboratory has pioneered the use of robotic high-throughput methods of drug discovery to identify new targets for heart failure. According to co-lead study authors Christine Wahlquist and Agustin Rojas Muñoz, Ph.D., developers of the approach and researchers in Mercola's lab at Sanford-Burnham, they used high-throughput robotics to sift through the entire genome for microRNAs involved in heart-muscle dysfunction.

Subsequently, the researchers at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai found that injecting a small piece of RNA to inhibit the effects of miR-25 dramatically halted heart-failure progression in mice. In addition, it also improved their cardiac function and survival.

"In this study, we have not only identified one of the key cellular processes leading to heart failure, but have also demonstrated the therapeutic potential of blocking this process," said co-lead study author Dongtak Jeong, Ph.D., a post-doctoral fellow at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai in the laboratory of the study's co-senior author Roger J. Hajjar, M.D.

Nearly six million Americans suffer from heart failure, which is when the heart becomes weak and cannot pump enough blood and oxygen throughout the body. Heart failure is a leading cause of hospitalization in the elderly. Often, a variety of medications are used to provide heart-failure patients temporary relief of their debilitating symptoms. However, these medications do not improve cardiac function or halt the progression of the disease.

"Currently, heart-failure medications do not effectively address the underlying mechanisms that weaken contractile function and lead to the enlargement of heart-muscle cells," said co-senior study author Roger J. Hajjar, M.D. "Our study provides us with the key evidence we need to begin developing miR-25 as an important new therapeutic target, while adding our successful technique to block this microRNA to our growing arsenal of promising heart-failure therapies that we will further develop and test in future clinical trials."

Currently, Hajjar's laboratory is developing novel gene therapies for patients with heart failure. One therapy, currently in phase IIb/III human clinical trials, uses a modified viral vector to deliver a gene that produces SERCA2a, an enzyme found in healthy heart-muscle cells. Another therapy in preclinical development uses a disabled virus to deliver a gene called SUMO-1, which shrinks enlarged heart-muscle cells and improves cardiac function.

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About Sanford-Burnham Medical Research Institute

Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of diseases and devising the innovative therapies of tomorrow. Sanford-Burnham takes a collaborative approach to medical research with major programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory and childhood diseases. The Institute is recognized for its National Cancer Institute-designated Cancer Center and expertise in drug discovery and stem-cell technologies. Sanford-Burnham is a nonprofit, independent institute that employs 1,200 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at http://www.sanfordburnham.org.

About the Mount Sinai Health System

The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven member hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community-based facilities to tertiary and quaternary care.

The System includes approximately 6,600 primary and specialty care physicians, 12 minority-owned free-standing ambulatory surgery centers, over 45 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island, as well as 31 affiliated community health centers. Physicians are affiliated with the Icahn School of Medicine at Mount Sinai, which is ranked among the top 20 medical schools both in National Institutes of Health funding and by U.S. News & World Report. For more information, visit http://www.mountsinai.org/.

About the UC San Diego Jacobs School of Engineering

The UC San Diego Jacobs School of Engineering is a premier research organization dedicated to educating tomorrow's technology leaders and conducting leading edge research that drives innovation for the benefit of society. The Jacobs School's Department of Bioengineering is ranked in the top 3 of its kind in the nation, according to various rankings. The bioengineering department is a world leader, focused on the understanding, diagnosis and treatment of human disease through bioengineering analysis, systems biology and regenerative medicine.

Susan Gammon | EurekAlert!

Further reports about: Engineering Medicine SERCA2a Sinai function progression

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