Atherosclerosis: Research reveals new mechanism and therapeutic target
New research offers fresh insights into how a type of immune cell can destabilize the fatty deposits, or plaques, that form in arteries during atherosclerosis.
Atherosclerosis is a persistent, inflammatory condition in which plaques build up inside arteries, causing them to narrow and restrict blood flow.
When an atherosclerotic plaque bursts or breaks, it can trigger a heart attack or stroke.
Neutrophils are an abundant type of leukocyte (white blood cell) that defend against infection by attacking microbes. They also serve “many roles in inflammation.”
The new international study reveals that neutrophils can aggravate atherosclerosis by triggering a previously unknown type of cell death that destabilizes arterial plaques.
A recent Nature paper describes how neutrophils can induce a series of molecular events that also kills the smooth muscle cells that help to retain the plaques in the artery wall.
“Every inflammatory reaction,” says co-corresponding study author Prof. Oliver Söhnlein, from the Institute for Cardiovascular Prevention at the Ludwig Maximilian University (LMU) of Munich in Germany, “results in some collateral damage, because neutrophils also attack healthy cells.”
He and his colleagues have also designed and made a “tailored peptide” that could potentially target and block the cell-death process.
Arteries are vessels that supply the heart and other parts of the body with oxygen- and nutrient-rich blood, which cells need to function and live.
Atherosclerosis develops when various materials, such as cholesterol, fat, and cellular waste, deposit in the tissue lining the arteries. The deposits, or plaques, build up slowly over time causing the arteries to narrow and harden.
When arteries narrow, they impede blood flow and restrict the supply of oxygen and nutrients to cells. Depending on where it occurs, the restricted blood flow can result in heart disease, angina, carotid artery disease, peripheral artery disease, and chronic kidney disease.
The plaques themselves are also a risk. They can rupture, or pieces can break off, causing blockages. In addition, blockages can arise from blood clots that stick to the inner walls of narrowed arteries.
If the blockage is in an artery that supplies blood to the brain or the heart, it can result in a stroke or heart attack. Blockages in arteries that supply the legs can lead to tissue death, or gangrene.
According to statistics that the American Heart Association publish online, cardiovascular conditions, such as heart attack and stroke, were the primary cause of 840,678 deaths in 2016 in the United States.
Another feature of atherosclerosis is that it triggers signals that prompt the immune system to send neutrophils and other immune cells through the bloodstream to the plaques.
When they reach a plaque site, the immune cells slip between the endothelial tissue cells of the artery lining. At the same time, they release chemicals that signal to the immune system to send even more immune cells.
This can set up a cycle that turns the initial inflammation response into persistent, or chronic, inflammation. Once the inflammation becomes chronic, it raises the risk that the plaque will grow, rupture, and cause a blockage.
Using mouse models of atherosclerosis to investigate what goes on at cell level, the researchers discovered that neutrophils can play a particularly destructive role in destabilizing plaques.
“They bind to the smooth muscle cells that underlie the vessel wall, and are activated,” Prof. Söhnlein explains.
Once active, the neutrophils release “chromosomal DNA and its associated histones, which are highly charged and [toxic to cells],” he continues, adding: “Free histones kill nearby cells – in the case of atherosclerosis, smooth muscle cells.”
Histones are proteins that help to package DNA tightly inside chromosomes.
The histones kill the smooth muscle cells by causing pores to form in their walls. This allows extracellular fluids to seep through the pores into the cells, causing them to burst.
Because smooth muscle cells help to retain the plaques in the artery wall, their destruction causes the fatty deposits to become unstable and more likely to rupture and break.
In another part of the study, the team used molecular modeling to design a small protein molecule, or peptide, that could block the toxic effect of the free histones.
The authors suggest that the “histone-inhibitory peptide” could disrupt the histones by binding to them so that they cannot create pores in the cell membranes.
Prof. Söhnlein says that the synthetic peptide could have a similar effect on other conditions that involve chronic inflammation, such as chronic bowel inflammation and arthritis.
He and his co-authors conclude:
“Our data identify a form of cell death found at the core of chronic vascular disease that is instigated by leukocytes and can be targeted therapeutically.”