Improved cholesterol efflux by natural products

Atherosclerosis along with hypertension is the main cause of cardiovascular disease representing the number one cause of death in the world. Excessive cholesterol deposition in the atherosclerotic plaque and the formation of cholesterol-enriched proatherogenic macrophage foam cells is a critical step in the pathogenesis of atherosclerosis. Therefore enhancement of the export of cholesterol from macrophages, termed macrophage cholesterol efflux, results in an anti-atherosclerotic effect. Accordingly, this study overall aims to identify and characterize molecules that modulate this process as well as to contribute to a better understanding of the mechanisms regulating macrophage cholesterol efflux in general. Since macrophages are professional phagocytic cells of the innate immune system, we hypothesize that compounds effective and in (traditional) use against inflammatory disease might act via modulating macrophage functions. Preliminary studies examining a previously assembled collection of natural products isolated from medicinal plants traditionally used against inflammation identified three compounds with diverse chemical scaffolds as promising novel macrophage cholesterol efflux inducers: evodiamine, isolated from Evodia rutaecarpa; falcarindiol, isolated from Notopterygium incisum; and leoligin, isolated from Leontopodium alpinum. Consequently, we set the work focus of this proposal on the investigation of the molecular mechanism of action of evodiamine, falcarindiol, and leoligin by a combination of methods applied in vitro, in vivo, and in silico. Expected outcomes of this proposal are: 1. Characterization of the molecular mechanism of the cholesterol efflux-enhancing action of evodiamine, falcarindiol, and leoligin; and thus an 2. Increase in the basic knowledge for the mechanisms regulating macrophage cholesterol efflux in general (chemical biology approach).

Atherosclerosis along with hypertension is the main cause of cardiovascular disease representing the number one cause of death in the world. Excessive cholesterol deposition in the atherosclerotic plaque and the formation of cholesterol-enriched proatherogenic macrophage foam cells is a critical step in the pathogenesis of atherosclerosis. Therefore enhancement of the export of cholesterol from macrophages, termed macrophage cholesterol efflux, results in an anti-atherosclerotic effect. Accordingly, this study overall aimed to identify and characterize molecules that modulate this process as well as to contribute to a better understanding of the mechanisms regulating macrophage cholesterol efflux in general.The most interesting macrophage cholesterol efflux inducers which were identified and characterized in the course of the project include the small molecules evodiamine, falcarindiol, leoligin, bilirubin, isosilybin A, piperine, and erythrodiol. All of these molecules are derived from natural sources. Falcarindiol, piperine, and erythrodiol are present in food products; evodiamine, leoligin, and isosilybin A are found in medicinal plants; and bilirubin is a normal physiological constituent of the body.Interestingly, most of the studied molecules had different mechanisms of action, and their characterization resulted in the generation of new knowledge about the molecular mechanisms regulating macrophage cholesterol efflux.The knowledge that was accumulated in the project might help to better understand some of the effects which are induced in the body by specific food or herbal products. Moreover, the bioactive compounds and regulatory mechanisms characterized in this project could be used in the future for the development of dietary supplements or pharmaceuticals for prevention or therapy of cardiovascular diseases.