An international team coordinated by the CNC researcher Lino Ferreira, from the Faculty of Medicine of the University of Coimbra (FMUC) and from the Center of Neurosciences and Cell Biology, have found an enzyme (protein) that is involved in diseases related with vascular aging.
The results of the study, that started in 2012, were published in the Nature Communications journal and may contribute to the development of new drugs to combat diseases associated with premature and physiological aging.
During the project, researchers used cells from patients suffering from Hutchinson-Gilford Syndrome or Progeria – a rare disease characterized by early aging and premature death, usually caused by cardiovascular diseases, at around 14 years of age. This disease “is caused by a rare gene mutation, in the LMNA gene, that leads to the accumulation of an abnormal protein – progerina - in the cells. That protein is also observed during normal aging, although on a smaller scale”, says Patrícia Pitrez - first author of the paper.
“Since this project studies the pathological vascular aging (progeria), the knowledge generated is also of great importance in physiological vascular aging”, emphasizes Patrícia Pitrez.
The study focused on smooth muscle cells (found in blood vessels), since they are “the most affected in progeria, and there is a decrease in the number of these cells in aged arteries. But the cause for this loss was not known yet. We collected skin cells (fibroblasts) from progeria patients and from healthy individuals, reprogrammed them into stem cells and then differentiated these cells into smooth muscle cells”, explains the CNC researcher.
Then, to evaluate the mechanisms involved in the vascular biology, the team developed two vascular microchips – a healthy one and an aged one (progeria). Using these devices, it was possible to “maintain cells in arterial flow conditions, similar to the conditions existing in the arteries, and this allowed us to study the susceptibility of progeria cells in the laboratory. After a few days we saw a decrease in the number of progeria smooth muscle cells, but not in the healthy ones. Through this system it was possible to analyze the differences between the two microchips, comparing the two types of cells to understand why the number of cells decreases in progeria”, says Patrícia Pitrez.
And it was precisely while analyzing the differences between healthy and progeria cells that CNC researchers discovered “an enzyme – metalloproteinase 13 (MMP13) – whose concentration is about 30 times increased in progeria cells compared to the healthy ones”.
In an attempt to inhibit the action of this enzyme, the researchers also tested a drug, and were able to develop a specific therapy to counteract the decrease in the number of arterial cells that occurs in vascular aging.
Considering these results, the authors believe that “the administration of the drug in the early stages of the disease, combined with other drugs, previously tested and that reduce the amount of progerine, can add value to improve the patient’s quality of life and life expectancy”. On the other hand, they conclude, the microchip developed in the scope of this study “also brings new perspectives for the development of other treatments, not only for progeria patients, but also for physiological vascular aging”.
The project was co-funded by European funds – FEDER, through the COMPETE Program, and ERAatUC – and Portuguese funds, through Portuguese Foundation for Science and Technology (FCT). In addition to the University of Coimbra, researchers from the Institute of Molecular Medicine (Lisbon, Portugal), I-Stem (France), University of Aix-Marseille (France), Autonomous University of Barcelona (Spain), Molecular Genetics Laboratory (France), Francis Crick Institute (UK), University of Liverpool (UK), Leibniz Ageing Institute (Germany), AFM Telethon (France) and Cambridge Science Park (UK) participated in the research.
Credits: Cristina Pinto, Patrícia Pitrez, Lino Ferreira.