March 28, 2022—(BRONX, NY)—Speeding up a process that slows with age may protect against atherosclerosis, a leading cause of heart attacks and strokes. In findings published online this week in Proceedings of the National Academy of Sciences (PNAS), scientists at Albert Einstein College of Medicine led by Ana Maria Cuervo, MD, Ph.D., successfully minimized plaque from narrowing arteries in mice that would otherwise develop these lesions. The researchers did this by stimulating chaperone-mediated autophagy (CMA), a cellular housekeeping process that Dr. Cuervo discovered in 1993 and named 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 Dr Cuervo. , Professor of Developmental and Molecular Biology and Medicine. , holder of the 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.”
An impressive CMA CV
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 cell structures called lysosomes to be digested and recycled. Dr. Cuervo deciphered many molecular players involved in CMA and showed that CMA, through its rapid degradation of key proteins, regulates many intracellular processes, including glucose and lipid metabolism, circadian rhythms, and cell repair. DNA. She also 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, Alzheimer’s and Huntington’s disease.
Dr. Cuervo’s achievements were recognized in 2019 when she was elected to the National Academy of Sciences (NAS). In 1996, the NAS began inviting its newly elected members to submit a special inaugural paper to PNAS this would highlight the scientific contributions of the member. Due to delays related to the COVID-19 pandemic, today’s article on the protective role of CMA against atherosclerosis is Dr. Cuervo’s inaugural article. PNAS document and adds to its body of work on the importance of CMA.
Cardiovascular disease (CVD) is the leading cause of death worldwide, with more than 80% of these CVD deaths due to heart attacks and strokes. CVDs, in turn, are commonly associated with atherosclerosis: the buildup of plaque (a sticky material made of fat, cholesterol, calcium, and other substances) in the walls of arteries. Plaque buildup hardens and narrows the arteries, preventing them from supplying oxygenated blood to the heart muscle (resulting in heart attacks), the brain (strokes), and the rest of the body.
To investigate the role of CMA in atherosclerosis, Dr. Cuervo and colleagues promoted atherosclerosis in mice by feeding them a fatty Western diet for 12 weeks and monitoring CMA activity in the aortas of affected animals. of plate. CMA activity initially increased in response to dietary challenge; after 12 weeks, however, plaque accumulation was significant and virtually no CMA activity could be detected in the two cell types – macrophages and arterial smooth muscle cells – which are known to malfunction in atherosclerosis, resulting in plaque buildup in the arteries.
“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 stopped,” said said Dr. Cuervo. She noted that giving the high-fat diet to mice completely lacking CMA activity yielded even stronger evidence for the importance of CMA: plaques nearly 40% larger than those in control animals that also followed the CMA. high fat diet.
Of mice and also of men
Researchers have found evidence that low CMA activity is also correlated with atherosclerosis in humans. Some stroke patients undergo surgery, known as carotid endarterectomy, which removes segments of their carotid arteries affected by plaque to reduce the risk of a second stroke. Dr. Cuervo and colleagues analyzed CMA activity in carotid artery segments from 62 patients with first stroke who were followed for three years after their surgery.
“Patients with higher levels of CMA after their first stroke never had a second stroke, while second strokes occurred in almost all patients with low CMA activity,” Dr. 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.”
Increase AMC, eliminate atherosclerosis
The study is the first to show that the onset of AMC could be an effective way to prevent atherosclerosis from getting worse or progressing. The researchers genetically “upregulated” AMC in mice fed a pro-atherosclerotic high-fat Western diet and then compared them to control mice fed the same diet for 12 weeks. CMA-boosted mice had significantly improved blood lipid profiles, with markedly reduced cholesterol levels compared to control mice. The plaque lesions that formed in the genetically modified mice were significantly smaller and less severe than the plaques in the control mice. Fortunately, people won’t need genetic alteration to benefit from this discovery.
“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,” said Dr Cuervo. . Einstein has copyrighted this underlying technology.
The PNAS article is titled “Protective role of chaperone-mediated autophagy against atherosclerosis.” Other Einstein authors were Julio Madrigal-Matute, Ph.D., Dario F. Riascos-Bernal, Antonio Diaz, MD, Ph.D., Inmaculada Tasset, Ph.D., Adrian Martin-Segura, Ph.D ., Susmita Kaushik, Ph.D., Simoni Tiano, MD, Matthieu Bourdenx, Ph.D., Gregory J. Krause, MS, Nicholas Sibinga, MD, Fernando Macian, MD, Ph.D. and Rajat Singh, MD other corresponding co-authors are Judith C. Sluimer, Ph.D., of Maastricht University Medical Center in the Netherlands and the University of Edinburgh in the United Kingdom.
About Albert Einstein College of Medicine
The Albert Einstein College of Medicine is one of the nation’s leading centers for research, medical education, and clinical investigation. In the 2021-22 academic year, Einstein is home to 732 medical students, 190 doctoral students. students, 120 students in the combined MD/Ph.D. program and approximately 250 postdoctoral researchers. The College of Medicine has over 1,900 full-time faculty members located on the main campus and at its clinical affiliates. In 2021, Einstein received more than $185 million in awards from the National Institutes of Health. This includes funding for major Einstein research centers in cancer, aging, intellectual developmental disorders, diabetes, clinical and translational research, liver disease and AIDS. Other areas in which the College of Medicine focuses its efforts include research in brain development, neuroscience, heart disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore, University Hospital and Einstein University Medical Center, advances clinical and translational research to accelerate the rate at which new discoveries become the treatments and therapies that benefit patients. For more information, visit einsteinmed.org, read our blog, follow us on TwitterLike us on facebook, and watch us on YouTube.
Proceedings of the National Academy of Sciences
The title of the article
Protective role of chaperone-mediated autophagy against atherosclerosis
Publication date of articles
March 28, 2022