Supercharged cellular cleaning process prevents clogged arteries in mice
Researchers at the Albert Einstein College of Medicine have discovered a new potential way to prevent arteries clogging, and as such reduce the risk of heart attacks and strokes. The technique involves ramping up a cleaning process that naturally slows down as we age.
The key to the study is a process known as chaperone-mediated autophagy (CMA), which degrades damaged or unneeded proteins. In doing so, CMA regulates several important processes such as cellular metabolism, circadian rhythms and DNA repair, usually in response to cellular stress. Unfortunately, its effectiveness slows down with age, and the resulting build-up of proteins can contribute to some all-too-familiar age-related diseases, including Alzheimer's.
In the new study, the researchers identified a new health problem that CMA protects against – atherosclerosis, the build-up of plaque in arteries that can lead to heart attacks and strokes. The team found that CMA is activated in response to the cellular stress of high-fat diets and initially works to slow plaque accumulation, but over time it loses out.
“We’ve shown in this research that we need CMA to protect against atherosclerosis, which becomes severe and progresses when CMA declines – something that also happens when people get older,” said Dr. Ana Maria Cuervo, lead author of the study. “But equally important, we’ve proven that increasing CMA activity can be an effective strategy for curbing atherosclerosis and halting its progression.”
The team examined CMA’s role in the condition by first feeding mice a high-fat diet for 12 weeks, and monitored CMA activity in two cell types that malfunction in atherosclerosis. CMA activity was seen to ramp up during the early stages in response to the stress of the unhealthy diet, but intriguingly, by the 12-week mark there was almost no CMA activity in those cells.
In other tests, the researchers repeated the experiment on mice that had been engineered to lack any CMA activity at all. And sure enough, after 12 weeks on the high-fat diet they developed plaques that were almost 40 percent bigger than those of control mice eating the same food.
To test the inverse, the researchers engineered mice with higher CMA activity, and after the same amount of time on the high-fat diet they had better blood lipid profiles, far lower levels of cholesterol, and significantly smaller and less severe plaques, compared to control mice.
Of course, mouse biology is very different to humans, so it’s not a given that the same mechanism is at work in our bodies too. However, the researchers did find some evidence linking CMA to atherosclerosis in humans, by analyzing CMA activity in clogged artery segments removed from 62 patients that had suffered a stroke.
“Those patients with higher levels of CMA following their first strokes never got a second one, while second strokes occurred in nearly all the patients with low CMA activity,” said Cuervo. “This suggests that your CMA activity level post-endarterectomy could help in predicting your risk for a second stroke and in guiding treatment, especially for people with low CMA.”
The researchers say they’ve developed drug compounds that show promise in boosting CMA activity in human-derived cells, so hopefully with further development this could lead to new treatments to reduce atherosclerosis and prevent heart attacks and strokes. The same team is also investigating how boosting CMA could help treat other conditions like Alzheimer's.
The research was published in the journal PNAS.