Activin Receptor 2: a potential target for the treatment of cardiometabolic disease
Thesis event information
Date and time of the thesis defence
Place of the thesis defence
Auditorium F202 of the Faculty of Medicine (Aapistie 5B)
Topic of the dissertation
Activin Receptor 2: a potential target for the treatment of cardiometabolic disease
Doctoral candidate
MSc, BVSc/Veterinarian Julia Swan
Faculty and unit
University of Oulu Graduate School, Faculty of Medicine, Research Unit of Biomedicine and Internal Medicine, Biocenter Oulu
Subject of study
Medicine
Opponent
Associate Professor Kirsi Virtanen, University of Turku
Custos
Docent Johanna Magga, Research Unit of Biomedicine and Internal Medicine, Biocenter Oulu
Growth factors of the TGFbeta family as therapeutic targets in cardiometabolic disease
Cardiovascular diseases are the leading cause of mortality worldwide. People with excess weight or obesity (body mass index greater or equal to 35kg/m2) have an increased risk of
developing heart disease. In 2023, a report from the World Obesity Atlas projected that over 4 billion individuals, or 51% of the global population, will develop obesity by 2035. As a result, obesity and its related diseases are now considered among the top public health issues facing the world today.
Recently, a pharmaceutical which blocks activin receptor 2 (ACVR2) signalling has been shown to target muscle and fat, helping patients to lose weight. We wanted to investigate whether blocking ACVR2 could also treat obesity-related heart disease. To do this, mice were fed a high-sugar, high-fat diet and they were given a hypertensive agent. This mimics the metabolic state which impedes cardiac function and may lead to obesity-related heart failure. Within two months, the mice treated with the ACVR2 signalling blocker had healthier hearts, lowered blood cholesterol, did not develop fatty liver disease, and were metabolically healthier than the mice that did not receive pharmaceutical treatment.
In the lab, we also treated cells with the ligands of TGFbeta family that stimulate ACVR2
signalling. We found that increased activation of ACVR2 signalling may harm cardiac cells over time. ACVR2 activation impaired blood vessel formation, which is important for keeping the heart muscle oxygenated and nourished. The transport of fatty acids, the heart's main energy source, also decreased after ACVR2 signalling stimulation. We also found that the activation of ACVR2 signalling initiated the transition of endothelial cells to mesenchymal type, potentially inducing fibrosis. Finally, we found that ACVR2 activation overstimulated the cardiac fibroblasts. Under normal circumstances, these cells help with wound healing, by replacing injured tissue with collagen. However, when overstimulated, fibroblasts may produce excess extracellular matrix which disrupts the normal heart architecture, making it stiff and unable to function properly.
Taken together, ACVR2 may be a potential pharmaceutical target for treating obesity-related heart diseases. This could help people to lose weight and improve their metabolic and heart health.
developing heart disease. In 2023, a report from the World Obesity Atlas projected that over 4 billion individuals, or 51% of the global population, will develop obesity by 2035. As a result, obesity and its related diseases are now considered among the top public health issues facing the world today.
Recently, a pharmaceutical which blocks activin receptor 2 (ACVR2) signalling has been shown to target muscle and fat, helping patients to lose weight. We wanted to investigate whether blocking ACVR2 could also treat obesity-related heart disease. To do this, mice were fed a high-sugar, high-fat diet and they were given a hypertensive agent. This mimics the metabolic state which impedes cardiac function and may lead to obesity-related heart failure. Within two months, the mice treated with the ACVR2 signalling blocker had healthier hearts, lowered blood cholesterol, did not develop fatty liver disease, and were metabolically healthier than the mice that did not receive pharmaceutical treatment.
In the lab, we also treated cells with the ligands of TGFbeta family that stimulate ACVR2
signalling. We found that increased activation of ACVR2 signalling may harm cardiac cells over time. ACVR2 activation impaired blood vessel formation, which is important for keeping the heart muscle oxygenated and nourished. The transport of fatty acids, the heart's main energy source, also decreased after ACVR2 signalling stimulation. We also found that the activation of ACVR2 signalling initiated the transition of endothelial cells to mesenchymal type, potentially inducing fibrosis. Finally, we found that ACVR2 activation overstimulated the cardiac fibroblasts. Under normal circumstances, these cells help with wound healing, by replacing injured tissue with collagen. However, when overstimulated, fibroblasts may produce excess extracellular matrix which disrupts the normal heart architecture, making it stiff and unable to function properly.
Taken together, ACVR2 may be a potential pharmaceutical target for treating obesity-related heart diseases. This could help people to lose weight and improve their metabolic and heart health.
Last updated: 12.2.2024