Foul-smelling chemical may keep atherosclerosis at bay

New research in mice suggests that a compound responsible for the odor of rotting flesh can shrink the fibrous plaques that build up in the walls of arteries in atherosclerosis.

The researchers discovered that this chemical, which is called putrescine, encourages a type of immune cell to engulf dead cells in the plaques.

Usually, immune cells called macrophages consume dead cells within minutes of them dying. However, if this housekeeping is inefficient, the dead tissue can trigger chronic inflammation.

Inflammation is a feature of not only atherosclerosis but also many other common conditions, including Alzheimer’s disease, asthma, lupus, and chronic lung disease.

The recent discovery, which features in the journal Cell Metabolism, could lead to new treatments.

“It’s estimated that a billion cells die in the body every day, and if you don’t get rid of them, they can cause inflammation and tissue death,” says Prof. Ira Tabas of Columbia University Vagelos College of Physicians and Surgeons in New York City, NY, who led the research.

Macrophages remove dead cells in a process called efferocytosis. This name comes from the Latin word efferre, which means “to carry to the grave.” If this process does not work efficiently, it can cause a buildup of dead cells. There is some evidence to suggest that these dead cells may support the growth of the plaques associated with atherosclerosis.

Effects of atherosclerosis 

In atherosclerosis, initial damage to the arterial wall leads to the accumulation of low-density lipoprotein (LDL or “bad”) cholesterol, immune cells, calcium, dead cells, and other debris. Over time, the plaque may build up, narrowing the artery and reducing the flow of oxygenated blood around the body.

Depending on their location, clogged arteries can cause:

  • angina as a result of coronary heart disease
  • peripheral artery disease (impaired circulation in the legs)
  • chronic kidney disease
  • carotid artery disease (impaired blood supply to the brain)

Blood clots sometimes form at the site of the plaques, further narrowing the artery. Clots and fragments of plaque can also break free and block arteries elsewhere in the body.

When an artery supplying the heart or brain becomes completely blocked, this will trigger a heart attack or stroke, respectively.

Atherosclerosis is a contributing factor in an estimated 50% of all deaths in Western countries, so finding new treatments is crucial.

Eating a healthful diet, exercising regularly, giving up smoking, and drinking less alcohol can help prevent it. However, it is difficult to shrink advanced plaques once they have become established.

How putrescine resolves inflammation 

By learning more about the natural mechanisms of plaque formation and the clearance of dead cells, Prof. Tabas and his colleagues hope to inspire the development of new kinds of treatment.

In their first experiment, they mixed human macrophages and dying cells in a dish to study the biochemistry of the process. They found that when the macrophages engulfed dead cells, they recycled the cells’ amino acids (the building blocks of proteins), including arginine.

The macrophages used an enzyme called arginase 1 to help convert the arginine to putrescine, which then triggers a chain reaction by signaling to other macrophages to consume more dead cells.

Having identified the role of putrescine, the scientists investigated its effect in mice with atherosclerosis. They discovered that in mice with worsening plaques, insufficient arginase 1 meant that putrescine was in short supply.

“But when we put putrescine in the animals’ drinking water, their macrophages got better at eating dead cells, and the plaques improved.”

– Prof. Ira Tabas

He continues, “Fortunately, when you dissolve putrescine into water, at least at the dosages needed to improve the plaques, it no longer gives off its odor. The mice drank it without any problem and show no signs of sickness.”

New treatments for chronic inflammation 

Prof. Tabas told Medical News Today that the discovery may inspire new treatments, not just for atherosclerosis but also for other conditions in which chronic inflammation plays a role, such as Alzheimer’s disease.

“Resolving inflammation is a normal part of the inflammatory response, and in these diseases, it doesn’t resolve,” he said.

Failure to get rid of dead cells through efferocytosis contributes to this, so a drug that promotes the clean-up operation could help reduce chronic inflammation.

However, putrescine itself may not be an ideal treatment, Prof. Tabas added, because previous research suggests that it is toxic at high doses.

“If this were ever to go to clinical trials, there would have to be very careful safety studies making sure that the doses needed to protect this pathway are far below those that cause toxicity,” he said.

The good news, Prof. Tabas concluded, is that other molecules that promote efferocytosis are already in clinical trials for other conditions.

They are known as “specialized pro-resolving mediators” or SPMs for short. The body generates them naturally through the breakdown of omega-3 fatty acids, which may help explain these nutrients’ potential health benefits.

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