Inflammation in atherosclerosis
We have studied the role of inflammatory mediators in development of atherosclerosis for many years. In 2018, one of our inflammatory focuses has been on the cysteine protease legumain. We have shown that legumain is increased in both plasma and plaques of patients with carotid stenosis and that legumain is produced by macrophages, and colocalized to macrophages in the plaque. We are currently elucidating the function and role of legumain in macrophage-induced inflammation in clinical atherosclerosis.
Obesity increases the risk of several metabolic conditions, with type 2 diabetes as one of its most devastating consequences. The term “metabolic healthy obese” has emerged the last years, describing those who develop severe obesity without metabolic sequela. Understanding the underlying mechanism for metabolic healthy and unhealthy obesity is of great interest to develop better treatment for this patient group. One of our major research projects is the study of T cell function in metabolic regulation during obesity development. Circulating and tissue resident T cells can modulate macrophage function and adipocyte differentiation, and thereby affect energy storage and utilization, resulting in healthy or dysregulated metabolism. This will further result in metabolic health or disease. To study this interaction we use a transgenic mouse with altered T cell function, as well as blood, adipose tissue and immune cells from patients with metabolic healthy and unhealthy obesity. We also address the relationship between metabolic healthy and unhealthy obesity and atherosclerotic risk.
Oxidative DNA damage and repair enzymes in atherosclerosis
The recent years, a main focus of the research group has been on oxidative DNA repair enzymes and their role in atherosclerosis. Enhanced generation of reactive oxygen species (ROS) is an important feature of atherosclerosis, induced by etiologic risk factors such as smoking and metabolic disturbances as well as their common final pathway, inflammation. Although ROS generation is a fundamental component of cellular metabolism and signal transduction, enhanced ROS generation may induce increased inflammation, cellular damage and apoptosis as well as DNA instability. If the ROS-induced damage on cellular DNA is not counteracted, it may promote cellular damage and apoptosis within the atherosclerotic lesion leading to plaque instability. Preliminary data from our group indicate that the DNA glycosylase Neil3 could serve as a sensor of metabolic stress, linking metabolic disturbances to atherosclerotic plaque development. Our hypothesis is that Neil3 modulates the development of atherosclerosis through epigenetic mechanisms, and the last year we have started a new major animal study to explore this hypothesis.