NOVA Medical School scientists uncover the surprising role of glucosylated cholesterol in atherosclerosis, opening the door to novel diagnostics and therapies.
A groundbreaking study has identified a lesser-known lipid, glucosylated cholesterol (GlcChol), as a key player in the development and progression of atherosclerosis - a major cardiovascular disease and underlying cause of heart attacks and strokes. The discovery sheds new light on how macrophages – the key immune cells involved in atherosclerotic plaque formation and inflammation - become dysfunctional, offering a promising target for future cardiovascular therapies and diagnostics.
The research, published in the prestigious Journal of Lipid Research, was led by André Marques, assistant researcher at the Lysosomes and Disease Laboratory at NOVA Medical School, and was inspired by parallels between lipid accumulation seen in certain lysosomal storage disorders (LSDs) and in atherosclerotic plaques. “We wondered if a similar mechanism of lipid overload, namely with the formation of GlcChol, might be affecting macrophages in human atherosclerotic lesions.” – the first-author of the study explained.
The findings reveal that GlcChol is not only present in human atherosclerotic lesions but is significantly enriched in macrophage-derived foam cells. Using both human tissue samples and mouse models, the team found that GlcChol accumulation is associated with oxidative stress, DNA damage, cell cycle arrest and impaired inflammatory responses in these cells, with direct implications for cardiovascular disease pathology.
Even more striking, patients who had suffered a myocardial infarction exhibited elevated levels of GlcChol relative to cholesterol in their blood, suggesting a systemic role and potential use as a biomarker for acute cardiovascular events.
“This isn’t just a passive by-product,” André Marques emphasized. “GlcChol actively contributes to the pathological cellular changes that drives the transformation of macrophages in plaques and the progression of the disease.”
While further research is needed to unravel the full biological pathways and therapeutic potential of GlcChol, this discovery marks an important step toward rethinking how we understand and approach cardiovascular disease. By shedding light on a previously overlooked lipid, the study opens up exciting avenues for innovation in both diagnostics and treatment - with implications that may extend far beyond cardiovascular diseases.
The study was authored by a multidisciplinary team from NOVA Medical School, Lisbon: André R.A. Marques, Inês S. Ferreira, Quélia Ribeiro, Elizeth Lopes, Daniela Pinto, José Ramalho, Manuel S. Almeida, Winchil L.C. Vaz, and Otília V. Vieira, as well as several collaborators from other institutions in Portugal and abroad.