ABSTRACT
The rising incidences of atherosclerosis have necessitated efforts to identify novel targets for therapeutic interventions. In the present study, we observed increased expression of the mechanosensitive calcium channel Piezo1 transcript in mouse and human atherosclerotic plaques, correlating with infiltration of PIEZO1-expressing macrophages. In vitro administration of Yoda1, a specific agonist for PIEZO1, led to increased foam cell apoptosis and enhanced phagocytosis by macrophages. Mechanistically, PIEZO1 activation resulted in intracellular F-actin rearrangement, elevated mitochondrial ROS levels and induction of mitochondrial fragmentation upon PIEZO1 activation, as well as increased expression of anti-inflammatory genes. In vivo, ApoE-/- mice treated with Yoda1 exhibited regression of atherosclerosis, enhanced stability of advanced lesions, reduced plaque size and necrotic core, increased collagen content, and reduced expression levels of inflammatory markers. Our findings propose PIEZO1 as a novel and potential therapeutic target in atherosclerosis.
Subject(s)
Apoptosis , Atherosclerosis , Foam Cells , Ion Channels , Macrophages , Phagocytosis , Animals , Ion Channels/metabolism , Ion Channels/genetics , Atherosclerosis/metabolism , Atherosclerosis/pathology , Atherosclerosis/genetics , Mice , Foam Cells/metabolism , Foam Cells/pathology , Humans , Macrophages/metabolism , Mice, Inbred C57BL , Thiophenes/pharmacology , Male , Reactive Oxygen Species/metabolism , Plaque, Atherosclerotic/pathology , Plaque, Atherosclerotic/metabolism , Plaque, Atherosclerotic/genetics , Mitochondria/metabolism , Pyrazines , ThiadiazolesABSTRACT
Lipid droplets are the essential organelle for storing lipids in a cell. Within the variety of the human body, different cells store, utilize and release lipids in different ways, depending on their intrinsic function. However, these differences are not well characterized and, especially in the context of ageing, represent a key factor for cardiometabolic diseases. Whole body lipid homeostasis is a central interest in the field of cardiometabolic diseases. In this review we characterize lipid droplets and their utilization via autophagy and describe their diverse fate in three cells types central in cardiometabolic dysfunctions: adipocytes, hepatocytes, and macrophages.