Mouse studies shed light on how protein controls heart failure

October 18, 2017, Johns Hopkins University School of Medicine
heart
Human heart. Credit: copyright American Heart Association

A new study on two specially bred strains of mice has illuminated how abnormal addition of the chemical phosphate to a specific heart muscle protein may sabotage the way the protein behaves in a cell, and may damage the way the heart pumps blood around the body.

The authors of a report on the new study, published in the September issue of Circulation: Heart Failure, say the work adds clarity to existing research about the role of protein modification in human , and suggests new strategies for personalizing treatment for a form of by examining phosphorylation.

"What the animal studies are telling us is that different individuals may have more or less altered phosphorylation that might help us someday identify patients who may benefit from targeted therapies," says Anne M. Murphy, M.D., professor of pediatrics at the Johns Hopkins University School of Medicine and the paper's senior author. Murphy is also part of the Johns Hopkins Children's Center.

"Oftentimes people talk about personalized medicine in terms of DNA markers, but this study highlights the potential for using protein markers directly to tailor care," she adds.

A form of heart disease known as heart failure with preserved ejection fraction (the amount of blood squeezed out when the heart contracts) impairs the heart's ability to quickly and efficiently relax between "beats," overworking the organ. The disease is estimated to impair circulation in more than 23 million people worldwide. Typical symptoms that people with heart failure experience include shortness of breath, but those with the form in which the ejection fraction is preserved at baseline have particular difficulty when they try to increase their activity or exercise. Heart failure with preserved does not respond well to common heart failure medications. The condition is common in adults, though some children with genetic disorders of heart muscle proteins share features of this condition.

In Murphy's previous research, she and colleagues found that heart failure was associated with changes in through altered phosphorylation in the heart muscle protein cardiac troponin I (cTnI), which helps regulate heart contraction. Murphy found that phosphorylation at a specific site on the protein, cTnI Serine 199, in humans was nearly twofold higher in people with heart failure than those without heart failure.

To sort out whether the increase was directly involved or only linked to impaired heart function, Murphy sought to understand the mechanism by creating two strains of mice, one with hyperphosphorylation of the mouse-analogous cTnI Serine 199 site and one in which phosphorylation of the site was turned off altogether.

In the experiment's first phase, Murphy and colleagues examined the function of the mouse hearts—through echocardiography as well as measurements with tiny catheters placed in the heart—compared to mice without this altered phosphorylation. At baseline the mice with hyperphosphorylation on this specific site experienced a longer time to heart relaxation and lower left ventricular peak filling rate (depressed diastolic function), but the amount of blood ejected during contraction was normal.

The researchers then stimulated both strains of mouse hearts with adrenaline to assess the impact of increased demand on the hearts. The mice with hyperphosphorylation had very limited ability to increase the ejection of blood from the heart compared to the controls in response to adrenaline. However, the mice with hyperphosphorylation did show some improvement in relaxation, though relaxation remained slower than controls at peak drug effect.

Finally, Murphy subjected both sets of mice to brief periods of reduced oxygen flow to the heart and then restored the flow of oxygen. Surprisingly, she reports, the hearts of with hyperphosphorylation were protected from this form of stress.

Currently, heart researchers are studying drugs that inhibit phosphorylation of proteins at specific sites. A specific enzyme called protein kinase C phosphorylates the cTnI 199 site. According to Murphy, while this approach has not been tested in human heart failure, the findings suggest that inhibiting a involved in phosphorylation may one day be a way to treat various heart disorders, including heart failure.

"We believe we have new evidence in animals that what we discovered in humans is significant and can someday be useful as a biomarker and someday may help us perform personalized therapy," adds Murphy.

Explore further: Blood cancer gene could be key to preventing heart failure

More information: Yuejin Li et al. Heart Failure–Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo, Circulation: Heart Failure (2017). DOI: 10.1161/CIRCHEARTFAILURE.117.003850

Related Stories

Blood cancer gene could be key to preventing heart failure

October 16, 2017
A new study, published today in Circulation, shows that the gene Runx1 increases in damaged heart muscle after a heart attack. An international collaboration led by researchers from the University of Glasgow, found that mice ...

Scientists reverse advanced heart failure in an animal model

October 4, 2017
Researchers have discovered a previously unrecognized healing capacity of the heart. In a mouse model, they were able to reverse severe heart failure by silencing the activity of Hippo, a signaling pathway that can prevent ...

Scientists identify protein linked to chronic heart failure

May 26, 2017
Researchers in Japan have identified a receptor protein on the surface of heart cells that promotes chronic heart failure. The study, "Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction," which ...

Researchers pinpoint new drug target for heart failure patients

April 4, 2017
Researchers led by Julian E. Stelzer, PhD, associate professor in the department of physiology and biophysics at Case Western Reserve University School of Medicine, have found a new target for drug developers seeking straightforward ...

Study examines altered gene expression in heart failure

August 4, 2017
Heart failure refers to a condition in which heart muscle becomes weakened over time, making it increasingly difficult for the heart to pump blood through the body like it should.

Ivabradine may not benefit certain heart failure patients

April 30, 2017
Researchers have completed a randomized clinical trial in patients with heart failure with preserved ejection fraction (HFpEF), which currently has no effective treatment for reducing morbidity and mortality.

Recommended for you

Higher risk of heart attack on Christmas Eve

December 12, 2018
The risk of heart attack peaks at around 10pm on Christmas Eve, particularly for older and sicker people, most likely due to heightened emotional stress, finds a Swedish study in this week's Christmas issue of The BMJ.

Your weight history may predict your heart failure risk

December 12, 2018
In a medical records analysis of information gathered on more than 6,000 people, Johns Hopkins Medicine researchers conclude that simply asking older adult patients about their weight history at ages 20 and 40 could provide ...

Age is the biggest risk for heart disease, but lifestyle and meds have impact

December 12, 2018
Of all the risk factors for heart disease, age is the strongest predictor of potential trouble.

New understanding of mysterious 'hereditary swelling'

December 12, 2018
For the first time ever, biomedical researchers from Aarhus University, Denmark, report cellular defects that lead to a rare disease, hereditary angioedema (HAE), in which patients experience recurrent episodes of swelling ...

Research team traces pathway to cardioprotection in post-ischemic heart failure

December 11, 2018
During an ischemic attack, the heart is temporarily robbed of its blood supply. The aftermath is devastating: reduced heart contractility, heart cell death, and heart failure. Contributing to these detrimental changes is ...

Macrophage cells key to helping heart repair—and potentially regenerate, new study finds

December 11, 2018
Scientists at the Peter Munk Cardiac Centre have identified the type of cell key to helping the heart repair and potentially regenerate following a heart attack.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.