Blocking key heart-failure culprit restores function

By Susan Gammon, Ph.D.
March 12, 2014

In a new collaborative research study, scientists were able to show how a tiny piece of RNA called miR-25 contributes to the progression of heart failure, and how they can block the process by inhibiting miR-25 to restore heart function. The study, performed by a team of cardiovascular researchers from Sanford-Burnham, Icahn School of Medicine at Mount Sinai, and UC San Diego, was published in the journal Nature on March 12, and suggests that miR-25 might be a new therapeutic target for restoring heart function.

“Prior to the study, we knew that the gene SERCA2a was down-regulated in heart failure, but we didn’t know the mechanism,” said Mark Mercola, Ph.D., professor in the Development, Aging, and Regeneration Program at Sanford-Burnham. “SERCA2a regulates the flow of calcium within heart muscle cells and is essential for proper cardiac contractile functions.”

Knowing that the heart’s ability to contract is regulated by calcium uptake, and that the activity of the calcium pump called SERCA2a is reduced in heart failure, Mercola and colleagues hypothesized that microRNAs that hamper SERCA2a function might be elevated in heart failure.

“Our study shows that a specific microRNA, called miR-25, is upregulated in patients with heart failure. And we show that injecting an agent that blocks miR-25 in a mouse model of heart failure improves function and survival to ‘normal’ levels,” said co-lead author and Ph.D. student Christine Wahlquist and postdoctoral researcher Agustin Rojas Muñoz, Ph.D., in Mercola’s lab at Sanford-Burnham.

Using a functional screening system, Wahlquist and Rojas Muñoz screened 875 microRNAs and found one, miR-25, that potently delayed calcium uptake in heart cells and was upregulated in both mice and humans.

Mercola’s collaborators at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai then found that injecting a small piece of RNA to inhibit the effects of miR-25 dramatically halted heart-failure progression in mice.

“In this study, we have not only identified one of the key cellular processes leading to heart failure, but also demonstrate the therapeutic potential of blocking this process,” said co-lead study author Dongtak Jeong, Ph.D., a postdoctoral fellow in the laboratory of Roger J. Hajjar, M.D., the study’s co-senior lead author and professor at Mount Sinai.

“Before the availability of high-throughput functional screening, our chance of teasing apart complex biological processes involved in diseases like heart failure was like finding a needle in a haystack,” said Mercola. “Our lab has pioneered the use of robotic high-throughput methods to identify new targets for heart failure. We are now able sift through the entire genome for microRNAs that interfere with heart-muscle function.”

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.

“This discovery represents a promising lead to develop drugs that work within failing heart-muscle cells and treat the disease itself—not just the symptoms,” said Mercola.

Dr. Mercola is also a professor of Bioengineering at UC San Diego.

A link to the paper can be found at:

A link to the article published by the Union Tribune San Diego can be found at:

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Susan Gammon, Ph.D.

Susan is editor of Communications at SBP.


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