Выборочное удаление 7-кетохлестерина новым атеросклерозным пациентом возвращает элементы пеноматериала в фенотип, похожий на макрофаж.
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Bhargava Prerna, Dinh Darren, Teramayi Fadzai, Silberg Ana, Petler Noa, Anderson Amelia M, Sadrerafi Keivan, Clemens Daniel M, O'Connor Matthew S
Аннотация
Оригинал публикации
Selective removal of 7-ketocholesterol by a novel atherosclerosis therapeutic candidate reverts foam cells to a macrophage-like phenotype.
BACKGROUND AND AIMS: The removal of the toxic oxidized cholesterol, 7-ketocholesterol (7KC), from cells through the administration of therapeutics has the potential to treat atherosclerosis and various other pathologies. While cholesterol is a necessary building block for homeostasis, oxidation of cholesterol can lead to the formation of toxic oxysterols with 7KC being the most prominent. 7KC is primarily formed through the non-enzymatic oxidation of cholesterol and is found in high levels in oxidized LDL (oxLDL) particles, which are highly implicated in heart disease. 7KC is implicated in the pathogenesis of numerous diseases, including multiple sclerosis, hypercholesterolemia, sickle cell anemia, and multiple age-related diseases. Of particular interest is the role of 7KC in the progression of atherosclerosis, with several studies associating elevated 7KC levels with the etiology and severity of the disease and in the underlying transition of macrophages to foam cells.
METHODS: This research aims to elucidate the molecular mechanisms of UDP-003, a novel therapeutic compound, in mitigating the harmful effects of 7KC in mouse and human monocyte and macrophage cell lines.
RESULTS: Experimental evidence demonstrates that administration of UDP-003 can reverse the foam cell phenotype, rejuvenating these cells by returning phagocytic function, preventing loss in efferocytosis ability, and decreasing both reactive oxygen species (ROS) and intracellular lipid droplet accumulation. We further demonstrate that UDP-003 drives urinary excretion of 7KC in vivo and has a safety/toxicity profile compatible with initiation of human clinical trials.
CONCLUSIONS: Our data suggest that the targeted removal of 7KC from foam cells with UDP-003 can potentially prevent and reverse atherosclerotic plaque formation. UDP-003 has the potential to be the first disease-modifying therapeutic approach to treating atherosclerotic disease.