ABOVE: Atherosclerosis, the thickening or hardening of blood vessels, is caused by a build-up of sticky plaques in the inner lining of arteries, seen here in this human coronary artery. Wikimedia Commons, Nephron

EDITOR’S CHOICE IN PHYSIOLOGY

When Maastricht University vascular biologist Judith Sluimer first learned that a cellular housekeeping process called chaperone-mediated autophagy (CMA) regulates fat metabolism, she saw an opportunity, she says. Ana María Cuervo, a cell biologist at Albert Einstein College of Medicine, discovered CMA in 1993, and Sluimer thought the pathway—through which lysosomes recycle used or damaged proteins—might also buffer against atherosclerosis, the thickening of arteries with fat-filled plaques. 

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Cuervo, Sluimer, and their colleagues found that CMA activity initially increased in mice fed a high-fat diet, but declined dramatically as the animals developed atherosclerosis, possibly because the rodents’ protein-recycling mechanisms became overwhelmed. Atherosclerosis was also exacerbated in mice genetically engineered to lack CMA activity: the animals developed large plaques, and their arterial smooth muscle cells, which ordinarily stabilize plaques, became defective. Switching on CMA lowered cholesterol and reduced plaque size, “so indeed, CMA was protective,” says Sluimer. 

The team also inspected carotid artery tissue from 62 people who had experienced a heart attack or stroke and found that those who later developed a second event all had lower CMA activity after the first. Sluimer says that although the samples captured only one time point, the result “gives us a strong clue” that CMA may defend against human atherosclerosis. 

Jason Kovacic, a cardiologist at the Victor Chang Cardiac Research Institute in Australia who was not involved in the work, says the study adds “a whole other element to atherosclerosis” for researchers to consider and opens the door to the possibility of new therapies that temporarily boost CMA activity to stabilize plaques prone to rupture. However, Kovacic cautions that “careful investigation” is needed to understand how upregulating CMA may perturb other cellular processes and if targeting CMA in vasculature cells alone is possible. 

J. Madrigal-Matute et al., “Protective role of chaperone-mediated autophagy against atherosclerosis,” PNAS, 119:e2121133119, 2022.