STUDY. A new study by researchers at Sahlgrenska Academy shows that blocking cleavage of the filamin A protein in white blood cells reduces the development of atherosclerosis in mice. The study also identifies a new principle for how cholesterol is metabolized in blood.
Hardening of the arteries, or atherosclerosis, arises when cholesterol is deposited on the inner walls of large and medium-sized arteries, where it can cause cardiovascular diseases and produce the serious clinical consequences such as heart attack.
“The atherosclerosis process begins early in life and then progress quietly for decades before it manifests itself as a heart attack or other acute clinical conditions. Today we try to prevent atherosclerosis through changes in diet and lifestyle and by using pharmaceuticals, but there is still no curative treatment,” says Levent Akyürek, a professor of pathology at Sahlgrenska Academy and physician at Sahlgrenska University Hospital.
Increased expression of filamin A
The deposits of cholesterol that form in atherosclerotic vessel wall attract macrophages—white blood cells that normally protect us by eating up bacteria and damaged or virus-infected cells.
“We discovered that the macrophages that accumulate in advanced atherosclerotic lesions of the carotid artery in patients express higher levels of a protein called filamin A than macrophages that accumulate in smaller lesions,” says Akyürek.
Regulates genes indirectly
Filamin A is a large, threadlike protein that provides cells with stability just like the skeleton in our body. In the article, published in the prestigious journal Circulation, researchers describe how filamin A splits into two parts and how this accelerates the atherosclerotic process. They also showed that when the cleavage of filamin A was blocked in the macrophages, the atherosclerosis decreased markedly in mice.
“We found that an enzyme called calpain cleaves filamin A into smaller fragments and that one of these fragments enters the cell nucleus, where it regulates the macrophage gene expression and the function of the cell. When we treated mice with a pharmaceutical that inhibits calpain, this inhibited the development of atherosclerosis,” says Akyürek.
Ideas for future treatments
When the researchers stopped the production of filamin A in the macrophages, this inhibited the mobility of the macrophages and the inflammatory activity. To the surprise of the researchers, the levels of cholesterol in the mice were also affected.
“Mice that lacked filamin A in macrophages had higher levels of cholesterol in the blood than mice in which filamin A remained. These results demonstrate a new principle for how the metabolism of cholesterol is regulated,” says Akyürek.
He adds, “This means we can greatly inhibit the development of atherosclerosis while cholesterol levels are elevated, at least in mice.”
The research team is now proceeding with its findings about the filamin A protein and its importance for atherosclerosis in the hope that the findings can provide new tools for future treatments.
Article: “Targeting filamin A reduces macrophage activity and atherosclerosis”
https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.119.039697
TEXT: ELIN LINDSTRÖM CLAESSEN
