The key to heart failure, new therapies on horizon

Some 5.8 million Americans suffer from heart failure, a currently incurable disease. But scientists at Temple University School of Medicine's (TUSM) Center for Translational Medicine have discovered a key biochemical step underlying the condition that could aid the development of new drugs to treat and possibly prevent it.

"Drugs we currently use for heart failure are not very effective," explained lead investigator Walter J. Koch, PhD, Professor and Chairman of the Department of Pharmacology at TUSM, and Director of the Center for Translational Medicine at TUSM. But, he added, "The more we learn about the disease mechanism, the more drug targets we'll find."

That is what Koch and colleagues at Thomas Jefferson University and the University of California, Davis, achieved in their latest study, which appears in the March 5 issue of the online journal PLOS ONE. The report is the first to show that an enzyme called GRK5 (G-protein coupled receptor kinase 5) can gain access to a heart cell's nucleus – its command center, where control of its genes is maintained – by way of a transport mechanism involving calcium and a protein known as calmodulin. Once calcium and calmodulin deliver GRK5 to the nucleus, the enzyme usurps control over specific genes, ultimately causing hypertrophy, in which heart cells grow larger in size. Hypertrophy is a biological hallmark of heart failure.

GRK5 had previously been identified as a key player in maladaptive cardiac hypertrophy, which is the end stage of heart failure, when the heart muscle becomes enlarged and unable to pump enough blood to keep vital organs functioning. While GRK5's ability to get inside the nucleus was known, Koch and colleagues worked to fill in the missing links in its transport mechanism. Those links, they hope, will not only allow them to better understand GRK5's role in causing heart cells to increase in size but also find ways to block that process to more effectively treat heart failure.

The GRK5 enzyme is a unique member of the GRK family, owing to its presence in the nucleus. Its journey begins at the cell membrane, where signals received by a molecule at the cell surface known as a Gq-coupled receptor prompt "escorts" – one of which is calmodulin, as the researchers discovered – to attach to GRK5 and guide it to the nucleus.

The team found that GRK5's transport requires calmodulin after examining different places on the enzyme where various escort molecules attach. They then introduced mutations that altered the attachment sites. Only when calmodulin-binding residues on GRK5 were mutated was the enzyme prevented from reaching the nucleus. Those mutations led to dramatic decreases in nuclear GRK5 levels and corresponding declines in the activity of genes known to drive cardiac hypertrophy. Calmodulin's ability to bind to GRK5 is in turn dependent on calcium. The same results were obtained both in vitro, using human heart muscle cells cultivated under laboratory conditions, and in vivo, in mice.

The team's research also marks a breakthrough in scientists' understanding of the role of neurohormones in hypertrophy. Released by specialized neurons into the bloodstream, neurohormones have long been cited as a cause of heart cell enlargement.

"One of the novel findings to fall out of this paper is that not all hypertrophic signals from neurohormones are the same," Koch explained. "That's something to keep in mind as we move forward."

The next step, according to Koch, is to test the ability of different agents to keep GRK5 out of the nucleus. "We are now discussing a trial on inhibition of another cardiac GRK, GRK2," he said. He cautioned, however, that trials in patients with GRK5 inhibition are years away. First, agents capable of blocking GRK5 transport must be identified and tested in animals.

The work is an important advance for Temple's Center for Translational Medicine. GRK5 enters the pipeline of novel drug targets under investigation by the Center's scientists and clinicians, who share the common goal of coordinating clinical practice and basic research to speed the delivery of new therapies to patients.

"It's another entry into larger, pre-clinical animal studies," Koch said. "Something new to start down the path of translational medicine."

Other researchers contributing to the work include Jessica I. Gold, Jeffrey S. Martini, and Jonathan Hullmann at the Center for Translational Medicine at Thomas Jefferson University; Erhe Gao, J. Kurt Chuprun, Douglas G. Tilley, and Joseph E. Rabinowitz at TUSM; and Julie Bossuyt and Donald M. Bers at the University of California, Davis.

The research was supported by NIH grants P01 HL091799 and P01 HL075443 and by a pre-doctoral Fellowship from the Great Rivers Affiliate of the American Heart Association.

Most Popular Now

Amgen announces Repatha® (evolocumab) significantl…

Amgen (NASDAQ:AMGN) has announced that the FOURIER trial evaluating whether Repatha® (evolocumab) reduces the risk of cardiovascular events in patients with clinically ev...

Read more

Vitamin D discovery could prove key to new treatme…

A team led by Motonari Uesugi, professor and deputy director of Kyoto University's Institute for Integrated Cell-Material Sciences (iCeMS), found that a vitamin D metabol...

Read more

Merck announces research collaboration with Domain…

Merck, a leading science and technology company, today announced it has entered into a collaboration and licensing agreement with Domain Therapeutics, Strasbourg, France...

Read more

AstraZeneca expands 1st-line lung cancer Immuno-On…

AstraZeneca has provided an update on its Immuno-Oncology (IO) late-stage clinical development programme in 1st-line non-small cell lung cancer (NSCLC), including a refin...

Read more

Nuts can inhibit the growth of cancer cells

Roasted and salted, ground as a baking ingredient or fresh from the shell - for all those who enjoy eating nuts, there is good news from nutritionists at Friedrich Schill...

Read more

The drugs don't work, say back pain researchers

Commonly used non-steroidal anti-inflammatory drugs, such as ibuprofen, used to treat back pain provide little benefit, but cause side effects, according to new research ...

Read more

Novo Nordisk enters collaboration with University …

University of Oxford and Novo Nordisk today announced a landmark research collaboration focused on type 2 diabetes. The partnership will enable scientists from Novo Nordi...

Read more

An alternative theory on how aspirin may thwart ca…

Studies abound that point to a role for plain old aspirin in keeping deadly cancers at bay. While aspirin is not yet part of mainstream treatment for any cancer, it is re...

Read more

Pfizer reports fourth-quarter and full-year 2016 r…

Pfizer Inc. (NYSE: PFE) reported financial results for fourth-quarter and full-year 2016 and provided 2017 financial guidance. Pfizer manages its commercial operations th...

Read more

Relationship expert teams up with Pfizer to addres…

Nationally-recognized relationship expert and author, Logan Levkoff, Ph.D., has partnered with Pfizer Inc. (NYSE:PFE) to fill a void in information available to people li...

Read more

Anti-inflammatory diet could reduce risk of bone l…

Anti-inflammatory diets - which tend to be high in vegetables, fruits, fish and whole grains - could boost bone health and prevent fractures in some women, a new study su...

Read more

Drug shows promise for treating alcoholism

UCLA researchers have found that an anti-inflammatory drug primarily used in Japan to treat asthma could help people overcome alcoholism. Their study is the first to eval...

Read more

Pharmaceutical Companies

[ A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Z ]