Cellular housekeeping process may protect against atherosclerosis

Findings from research led by a team at Albert Einstein College of Medicine suggest that speeding up a cellular housekeeping process that slows with age may protect against atherosclerosis. Ana Maria Cuervo, MD, PhD, and her colleagues successfully minimized plaque from narrowing arteries in mice that would otherwise develop these lesions, by stimulating chaperone-mediated autophagy (CMA), a process discovered by Cuervo in 1993 and to which he gave a name in 2000.

“We showed in this research that we need AMC to protect against atherosclerosis, which becomes severe and progresses when AMC declines, which also happens when people age,” said Cuervo, professor of Developmental and Molecular Biology and Medicine, Robert and Renée Belfer Chair for the Study of Neurodegenerative Diseases and Co-Director of the Einstein Institute for Aging Research. “But just as importantly, we have proven that increasing CMA activity can be an effective strategy to slow down atherosclerosis and halt its progression.”

Cuervo and colleagues reported their findings in Proceedings of the National Academy of Sciencess, in an article titled “Protective role of chaperone-mediated autophagy against atherosclerosisin which they concluded: “We propose that CMA could be an attractive therapeutic target against cardiovascular disease.

Cardiovascular disease (CVD) is the leading underlying cause of death worldwide, accounting for more than 31.5% of total deaths, the authors wrote. “Major risk factors for the development of atherosclerosis – the most common cause of CV clinical events – such as obesity, hypertension, diabetes and aging are increasing to epidemic proportions due to fashion changes of life and the growth of the elderly population.

Atherosclerosis is the buildup of plaque (a sticky material made up of fat, cholesterol, calcium, and other substances) in the walls of the arteries. Plaque buildup hardens and narrows the arteries, preventing them from supplying oxygenated blood to the heart muscle, brain, and other parts of the body, and can lead to heart attack and stroke.

CMA maintains the normal functioning of cells by selectively breaking down the numerous proteins contained in the cells. In CMA, specialized “chaperone” proteins bind to proteins in the cytoplasm and guide them to enzyme-filled lysosomes to be digested and recycled.

Cuervo’s research deciphered many molecular players involved in CMA and showed that this process regulates many intracellular processes, including glucose and lipid metabolism, circadian rhythms, and DNA repair. “CMA contributes to the regulation of energy homeostasis by rapidly degrading enzymes involved in glucose and lipid metabolism,” the authors continued. Cuervo had further discovered that disrupted CMA allows damaged proteins to build up to toxic levels, contributing to aging and – when toxic buildup occurs in nerve cells – to neurodegenerative diseases such as Parkinson’s disease, d Alzheimer’s and Huntington’s.

Her achievements were recognized in 2019 when she was elected to the National Academy of Sciences. Amid COVID-19 delays, new report on CMA’s protective role against atherosclerosis is its inaugural PNAS article, which adds to his body of work on the importance of CMA.

To investigate the role of CMA in atherosclerosis, Cuervo and colleagues promoted atherosclerosis in mice by feeding them a fatty Western diet for 12 weeks and then monitoring CMA activity in plaque-affected aortas. animals. Researchers found that CMA activity initially increased in response to food challenge, but after 12 weeks there was significant plaque accumulation and virtually no CMA activity could be detected in either cell type – macrophages and macrophages. arterial smooth muscle cells – which are known. dysfunction in atherosclerosis, leading to plaque buildup in the arteries. “We identified that CMA is regulated early in response to proatherogenic challenges and demonstrate that reduction in systemic CMA worsens vascular pathology in these conditions,” they wrote.

Cuervo commented, “CMA seemed to be very important in protecting macrophages and smooth muscle cells, helping them to function normally despite the pro-atherosclerotic diet, at least for a while, until their CMA activity subsided. stopped. She noted that feeding the high-fat diet (HFD) to mice completely devoid of CMA activity yielded even stronger evidence for the importance of CMA, and in these animals the plaques were nearly 40% larger than those of control animals that were also on the HFD. “…in vivo genetic blockade of CMA worsens atherosclerotic pathology through both systemic and cellular autonomic changes in vascular smooth muscle cells and macrophages, the two major cell types involved in atherogenesis,” wrote said the authors. The researchers separately reported evidence that low CMA activity correlates with atherosclerosis in humans. Some stroke patients undergo surgery known as carotid endarterectomy to remove plaque-affected segments of their carotid arteries and reduce the risk of a second stroke.

Ana Maria Cuervo, MD, PhD, Professor of Developmental and Molecular Biology and Medicine, Robert and Renée Belfer Chair for the Study of Neurodegenerative Diseases, and Co-Director of the Einstein Research Institute for Aging. [Albert Einstein College of Medicine]

Cuervo’s team analyzed CMA activity in carotid artery segments from 62 patients with first stroke who were followed for three years after their surgery. “Those patients with higher levels of CMA after their first strokes never had a second stroke, whereas second strokes occurred in almost all patients with low CMA activity,” Cuervo said. “This suggests that your CMA activity level after endarterectomy could help predict your risk of a second stroke and guide treatment, especially for people with low CMAs.” Presenting the results of their analyzes of human data, the team said: “These results confirm that atherosclerotic disease is also associated with dysfunctional AMC in the vasculature in humans.”

The team suggests that their study is the first to show that the onset of AMC could be an effective way to prevent atherosclerosis from getting worse or progressing. HFD-fed mice that were genetically engineered to upregulate CMA showed greatly improved blood lipid profiles, with markedly reduced cholesterol levels compared to HFD-fed control mice. The plaque lesions that formed in the genetically modified mice were also significantly smaller and less severe than the plaques in the control mice. “We show that genetic activation of CMA slows disease progression in mice, supporting a potential therapeutic value of CMA upregulation in atherosclerosis,” the team commented.

In their discussion, the team further commented, “We propose that upregulation of CMA is part of the body’s response to proatherogenic challenges, but that factors such as aging or sustained dietary pressure , known to inhibit CMA, reduce the effectiveness of this protective mechanism.”

Stimulation of CMA in humans may be pharmacologically possible, the authors noted. “My colleagues and I have developed drug compounds that have shown promise for safely and effectively increasing CMA activity in most mouse tissues and in cells of human origin,” Cuervo said. Einstein filed intellectual property on the underlying technology.