Diabetes accelerates the development ofatherosclerosis, increasing the incidence of cardiovascular events. In this terrible disease, immune cells called macrophages release molecules such as chemokines and cytokines, causing inflammation and leading to the formation of arterial plaques.
However, significant gaps remain in understanding the exact molecular mechanisms that control this increased inflammatory response in subjects with diabetes.
In a new preclinical study, researchers at Brigham and Women's Hospital, a founding member of the Mass General Brigham Health System, have identified a long noncoding RNA (lncRNA) sequence that may help them unravel the complex processes underlying a. diabetica, https://www.cell.com/cell-reports/fulltext/S2211-1247(24)00143-8potentially paving the way for future therapeutic interventions in humans.
The Work was published in Cell Reports.
Future therapeutic interventions that counteract diabetic atherosclerosis
Through the genetic analysis of a mouse model of a. diabetic, the research team identified a specific long non-coding RNA sequence, called MERRICAL, which is involved in the recruitment of macrophages into the arterial wall.
As atherosclerosis progressed in these mice, the researchers found a dramatic increase in MERRICAL expression in arterial lesions, areas where atherosclerotic plaque built up and damaged the arteries.
Furthermore, when the research team therapeutically administered inhibitors to reduce MERRICAL expression levels, they observed a striking reduction in macrophage recruitment, disease, and aortic lesion formation (74% in the aortic sinus and 86% in the descending aorta).
“Our work provides new insights into the targets that underlie altered vessel wall responses in diabetes and identifies a key therapeutic target for reversing the a
accelerated in diabetes,” said Mark W. Feinberg, MD, cardiologist and associate professor of medicine at UCLA. the Brigham's Heart and Vascular Center and Harvard Medical School, Boston.
Discovery of a new protein with an important role in atherosclerosis
Atherosclerosis is the underlying condition that causes heart attacks and strokes. Researchers from Radboudumc in the Netherlands have discovered a protein that appears to play an important role in the disease. The protein is called Prosaposin and its role in atherosclerosis was previously unknown.
Atherosclerosis is caused by cholesterol that builds up in the vessel wall and triggers chronic inflammation. Cholesterol-lowering drugs have been found to help treat the disease. Recent research has shown that inhibiting inflammation can also help prevent heart attacks and strokes. The challenge now is to find ways to inhibit inflammation specifically in disease, without hindering the rest of the body's defenses that protect us from infection.
The cells primarily responsible for inflammation in atherosclerosis are macrophages. The inflammatory activation of these cells is an energy-requiring process. The cells must therefore increase their metabolic rate considerably. “Unraveling how they do this gives us insights into how we can slow inflammatory activity and therefore reduce atherosclerosis.”
An international team of researchers, led by Raphaël Duivenvoorden from Radboudumc in the Netherlands, studied what happens when the macrophages' power is turned off. The main metabolic switch is a protein complex called mTOR. Using nanotechnology, they were able to specifically turn off this switch in macrophages and study its effect on atherosclerosis in a mouse model. “We saw after just one week of treatment that the atherosclerotic lesions shrank and the inflammation decreased.”
This result piqued their interest in unraveling the molecular mechanism underlying this powerful anti-inflammatory effect. Their analyzes consistently revealed an important role for a protein called Prosaposin. Its role in atherosclerosis was previously unknown. “In further experiments we found that prosaposin has an important effect on macrophage metabolism. We also observed less development of atherosclerosis and inflammation of vessel walls in mice that cannot produce prosaposin.”
To find out whether prosaposin also plays a role in atherosclerosis in humans, they studied its expression in human atherosclerotic lesions. “We observed substantial prosaposin expression by macrophages
in atherosclerotic plaques and this correlated with their inflammatory activity. This confirms that prosaposin plays a key role in atherosclerosis and is a potential new therapeutic target for the treatment of atherosclerosis.”
Proteins that regulate inflammation in atherosclerosis
The CARD8 protein regulates several inflammatory proteins in people with atherosclerosis. This is demonstrated by a new study by Örebro researchers published in the scientific journal Scientific Reports.
“We have demonstrated completely new functions associated with CARD8. These could be important in the future treatment of atherosclerosis and other inflammatory diseases,” says Örebro researcher Geena Paramel.
Atherosclerosis, also known as hardening of the arteries, is the main cause of most cardiovascular diseases. The inflammation of the blood vessel walls caused by atherosclerosis involves several proteins, which in turn are regulated by the CARD8 protein.
“Our study shows that CARD8 plays a crucial role in the inflammatory process of atherosclerosis,” says Geena Paramel, one of the researchers behind the study and senior lecturer in biomedicine at Örebro University.
The research team, led by Professor Allan Sirsjö from the Cardiovascular Research Center (CVRC) at Örebro University, examined the functions that CARD8 plays in cells lining the inside of blood vessels. By suppressing the CARD8 gene, they mapped which proteins regulate CARD8. The findings show a link between high levels of CARD8 and altered levels of several other inflammatory proteins in hardening of the arteries.
These results were confirmed in samples from a group of individuals suffering from atherosclerosis, in collaboration with researchers from the Karolinska Institutet.
“These findings are significant as they could be instrumental in the development of future drugs for atherosclerosis. In the future, we may be able to use more targeted drugs against CARD8 in atherosclerosis,” says Karin Franzén, professor of biomedicine at Örebro University and authors who contributed to the study.
In a previous study, researchers also observed a link in people who had a genetic variation in the CARD8 gene and altered levels of inflammatory proteins in the body.
“Many elements suggest that CARD8 may also be significant for many other inflammation-related diseases,” says Geena Paramel.
Identify the mechanism
The Örebro researchers are now planning a continued CARD8 study. In collaboration with BioReperia, a company from Linköping, they will continue to map the role that CARD8 plays in inflammatory processes that are also fundamental for tumor development.
“We currently know that CARD8 plays a crucial role in the inflammatory process in cells. We also want to understand how CARD8 influences other processes in cells,” explains Karin Franzén.
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