Repairing heart damage by targeting the stress response

12 March 2019

Arlene Weintraub / FiercePharma

When the heart is starved of oxygen during cardiac arrest, its muscle puts out stress signals that ultimately cause heart cells to die. The resulting damage often leads to chronic heart failure.

Now, a team of British scientists is proposing a new way to prevent that progression of disease, and it involves blocking the stress signals that lead to heart damage.

Researchers at Imperial College London discovered that a protein called MAP4K4 is activated in heart tissue when a heart attack produces stress signals. They designed a drug to block MAP4K4 and demonstrated that in mouse models it could reduce heart damage by about 60%. They reported the findings in the journal Cell Stem Cell.

The team started by studying cardiac tissue from people who had heart failure. They went on to show that MAP4K4 is not only activated in mice after heart attack, its also produced in human heart cells that are exposed to stress. The researchers created a heart attack in a dish with heart tissue grown from human stem cells. They found that raising levels of MAP4K4 made the cells more responsive to stress signals, they reported, while blocking it protected the cells.

When they tested their MAP4K4 blocker in mice, they wanted to recreate the typical treatment for people who have suffered heart attacks. So they restored the blood flow to the animals hearts and gave them the drug an hour later. It worked.

There are no existing therapies that directly address the problem of muscle cell death, said British Heart Foundation Professor Michael Schneider at Imperial Colleges National Heart and Lung Institutein astatement. Using both human cells and animals allows us to be more confident about the molecules we take forward.

Heart disease accounts for 1 in 4 deaths in the U.S., making it the leading cause of death, according to the Centers for Disease Control. Researchers in cardiovascular disease are investigating a range of approaches for reversing or preventing muscle damage after heart attack. Scientists atDukeand theUniversity of Torontoare working on a beating heart patchthat can restore function to damaged muscle, for example.

Last year, scientists at the Scripps Research Institute in La Jolla, California, fingered the protein GPR68 as a potential drug target in cardiovascular disease. The protein senses blood flow and promotes the dilation of arterioles, which are tiny blood vessels that help modulate blood pressure and flow.

The next step for the Imperial College-led team is to test different molecules that target MAP4K4, so they can refine a drug that will be suitable for testing in people. They believe theyll be ready to start a clinical trial in people by 2022.

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