Chemical that smells foul may keep atherosclerosis at bay

New research in mice suggests that a compound responsible for the smell of rotting flesh may shrink the fibrous plaques that atherosclerosis builds up in the walls of the arteries.

Atherosclerosis is the accumulation of plaque on the inside of blood vessel walls.
Atherosclerosis is the accumulation of plaque on the inside of blood vessel walls.

The researchers found that this drug, known as putrescine, causes a type of immune cell to swallow dead cells in the plaques.

The immune cells called macrophages normally destroy dead cells within minutes of death. If this housekeeping is ineffective, however, the dead tissue can cause chronic inflammation.

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

The latest discovery, which appears in the Cell Metabolism journal, may lead to new therapies.

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

In a process called efferocytosis, macrophages remove dead cells. The name comes from the Latin word efferre, meaning “to take to the grave.” If this process does not work efficiently, it can cause dead cells to build up. There is some suggestion that the formation of plaques associated with atherosclerosis may be aided by those dead cells.

Effects of atherosclerosis

For atherosclerosis, initial damage to the arterial wall causes low-density lipoprotein (LDL or “bad”) cholesterol, immune cells, calcium, dead cells, and other debris to accumulate. The plaque can build up over time, narrowing the artery and reducing the flow of oxygenated blood all around the body.

Clogged arteries can cause the folowing depending on their location:

  • 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)

Occasionally blood clots form at plaque sites, further narrowing the artery. Plaque clots and fragments can break free as well, and block arteries elsewhere in the body.

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

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

Eating a healthy diet, taking daily workouts, giving up smoking and consuming less alcohol will help prevent it. Nonetheless, it is hard to shrink advanced plaques once they are created.

How putrescine resolves inflammation 

Prof. Tabas and his colleagues are hoping to inspire the development of new types of treatment by learning more about the natural mechanisms of plaque formation and clearance of dead cells.

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

The macrophages used an enzyme called arginase 1 to help transform the arginine to putrescine, which then causes a chain reaction to kill more dead cells by signalling other macrophages to.

The scientists have established the function of putrescine, and have investigated its impact in atherosclerosis mice. We found that inadequate arginase 1 in mice with deteriorating plaques meant putrescine is 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, “Thankfully, when you dissolve putrescine into water, it no longer gives off its odor at least at the dosages required to improve the plaques. The mice drank it quickly and show no signs of illness.”

New treatments for chronic inflammation

Prof. Tabas told Medical News Today that the findings could inspire new treatments not only 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 it doesn’t resolve in these diseases,” he said.

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

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

“If this were ever to go through clinical trials, very thorough safety studies would have to be carried out ensuring that the doses needed to protect this pathway are far below those that cause toxicity,” he said.

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

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

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