TRPM2 Deletion Reduces Macrophage Dysfunction and Atherosclerosis in Mice
Atherosclerosis is a consequence of macrophage dysfunction. Macrophages are innate immune cells that help to remove excess cholesterol from blood vessel walls; cholesterol is primarily manufactured in the liver, and must travel through the bloodstream on LDL particles to reach the rest of the body. Macrophages help to retrieve unwanted cholesterol and return it to the bloodstream, attaching it to HDL particles for a return to the liver and excretion. This all works just fine in youth, but with age macrophages become inflammatory and dysfunctional, overwhelmed by cholesterol and the aged tissue environment, failing at their tasks and ultimately dying. This leads to growing fatty lesions in blood vessel walls, inflammatory macrophage graveyards that call in more immune cells to their deaths. Ultimately, one of these lesions ruptures, causing a heart attack or stroke. This kills more than a quarter of humanity.
Macrophages are large white blood cells that cruise through our body as a kind of clean-up crew, clearing hazardous debris. But in people with atherosclerosis - fatty deposits and inflammation in their blood vessels - macrophages can cause trouble. They eat excess fat inside artery walls, but that fat causes them to become foamy. And foamy macrophages tend to encourage inflammation in the arteries and sometimes bust apart plaques, freeing clots that can cause heart attack, stroke, or embolisms elsewhere in the body.
Changing how macrophages express a certain protein could prevent that kind of bad behavior. Researchers found that the protein, called TRPM2, is activated by inflammation. It signals macrophages to start eating fat. Since inflammation of the blood vessels is one of the primary causes of atherosclerosis, TRPM2 gets activated quite a bit. All that TRPM2 activation pushes macrophage activity, which leads to more foamy macrophages and potentially more inflamed arteries.
Researchers demonstrated one way to stop the cycle, at least in mice. They deleted TRPM2 from a type of lab mouse that tends to get atherosclerosis. Deleting that protein didn't seem to hurt the mice, and it prevented the macrophages from getting foamy. It also alleviated the animals' atherosclerosis. Researchers are now looking at whether increased TRPM2 expression in monocytes (circulating precursors of macrophages) in the blood correlates with severity of cardiovascular disease in humans.
Link: https://today.uconn.edu/2022/03/deleting-a-protein-in-mice-prevents-cardiovascular-disease/
Mmm but cholesterol would then accumulate in blood wessel walls, it isn't? What would do all that cholesterol there, mid term?
@Antonio
This is a very good question.
AFAIK the process is something like this: there's an inflammation on the vessel wall. An immune cell (probably a macrophage but needs fact checking) slaps a lipid patch on the site of inflammation (read glues some cholesterol). This is a like a quick fix before the cellular repair can take action. The cholesterol in the blood is in transported using two types of "vehicle" LPD - from the liver and and stomach to the blood and HDP from the blood to the liver for storage or to produce bile (the second is called Reverse cholesterol transport , and that's why it is HDP is called "good" cholesterol).
So far so good, a macrophage picks the cholesterol patch from the wall, packages it to HDP and mails it back to the liver. Still all good.
The problem appears when a macrophage cannot correctly process the cholesterol. Probably due to it being oxydated . In the process it release more inflammatory signals and attaches to the wall, where it might die or just stick there. This probably is a good defense mechanism in case of a vessel wall rupture. More macrophages come, slap more lipid patches and some of them die and contribute to the vicious circle. Of course, the cascade should not be running with a positive feedback loop or we would be dying at 40-50 in droves from heart attacks. So one iteration probably just adds a coat of extra cholesterol and foam cells. Then the foam cells might be covered with a vessel cells and for a while it is ok. Then the process gets triggered again and there's another layer added to the wall.
The whole process is dynamic , so sometimes the layers might be cleared up, and in the absence of inflammation or a much lower concentration of cholesterol the plaques not only stop growing but can even recede a bit.
So if we can find a medicine that can block the protein from the article (TRPM2) it reduces the inflammation cycle.
However, the initial lipid patches will stay on the artery wall. Here the test was done on mice prone to atherosclerosis. For those mice the net benefit of removed TRPM2 apparently outweighs the absence of removed patches. If some of the protein is still present, or there alternative pathways that might help cleaning the walls. Also, it might depend on the exact mechanism of plaque formation. For some groups temporarily reducing this protein might be quite helpful. For others it might not , or even be harmful.
Biochemistry works in mysterious ways. We still don't really know why metformin helps reducing blood sugar
Actually targeting this protein might indirectly help other diseases too. And even might be a promising treatment for Alzheimer's...
The TRPM2 gene is highly expressed in the brain and was implicated by both genetic linkage studies in families[8] and then by case control or trio allelic association studies in the genetic aetiology of bipolar affective disorder (Manic Depression).
...
role has been suggested for TRPM2 in activation of NLRP3 inflammasome, the dysregulation of which is strongly associated with a number of auto inflammatory and metabolic diseases, such as gout, obesity and diabetes.[13] In the brain it is involved in the toxicity of amyloid beta, a protein associated with Alzheimer's disease.[14] ...
https://en.wikipedia.org/wiki/TRPM2
Also...
https://www.sciencedaily.com/releases/2022/03/220328150520.htm
Source:
Albert Einstein College of Medicine
Summary:
Revving up a process that slows down as we age may protect against atherosclerosis, a major cause of heart attacks and strokes. Scientists have successfully minimized artery-narrowing plaque in mice that would otherwise develop those lesions. The researchers did so by boosting chaperone-mediated autophagy (CMA), a cellular housekeeping process.