Abstract
Simple SummaryCholesterol is the main sterol in mammals that is essential for healthy cell functionining. It plays a key role in metabolic regulation and signaling, it is a precursor molecule of bile acids, oxysterols, and all steroid hormones. It also contributes to the structural makeup of the membranes. Its homeostasis is tightly controlled since it can harm the body if it is allowed to reach abnormal blood concentrations. One of the diseases associated with elevated cholesterol levels being the major cause of morbidities and mortalities worldwide, is atherosclerosis. In this study, we have developed a model of the cholesterol metabolism taking into account local inflammation and oxidative stress. The aim was to investigate the impact of the interplay of those processes and cholesterol metabolism disturbances on the atherosclerosis development and progression. We have also analyzed the effect of combining different classes of drugs targeting selected components of cholesterol metabolism.Cholesterol is an essential component of mammalian cells and is involved in many fundamental physiological processes; hence, its homeostasis in the body is tightly controlled, and any disturbance has serious consequences. Disruption of the cellular metabolism of cholesterol, accompanied by inflammation and oxidative stress, promotes the formation of atherosclerotic plaques and, consequently, is one of the leading causes of death in the Western world. Therefore, new drugs to regulate disturbed cholesterol metabolism are used and developed, which help to control cholesterol homeostasis but still do not entirely cure atherosclerosis. In this study, a Petri net-based model of human cholesterol metabolism affected by a local inflammation and oxidative stress, has been created and analyzed. The use of knockout of selected pathways allowed us to observe and study the effect of various combinations of commonly used drugs on atherosclerosis. The analysis results led to the conclusion that combination therapy, targeting multiple pathways, may be a fundamental concept in the development of more effective strategies for the treatment and prevention of atherosclerosis.
Highlights
Complex biological phenomena have been studied from the point of view of systems science, resulting in the emergence of a rapidly developing branch of science called systems biology
The set of vertices is divided into two disjoint subsets in such a way that arcs can connect only vertices belonging to different subsets
Vertices belonging to the other subset are transitions and they correspond to active components of the system, which usually are some elementary processes
Summary
A complex network of interacting processes maintains cholesterol metabolism. These biological mechanisms should be seen and analyzed as a complex system using appropriate methods. Such methods have been developed for years in the area of systems sciences, mainly in the context of technical systems. The main motivation for investigating biological objects as complex systems is the growing belief that many crucial properties of these objects (e.g., organs, tissues, cells, processes, etc.) follow from properties of their elementary building blocks, and, or rather most of all, from structures of dens networks—of interactions among them [1]
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