PIEZO1 targeting in macrophages boosts phagocytic activity and foam cell apoptosis in atherosclerosis

Abstract The increasing prevalence of global atherosclerosis and its complications demand efforts to discover novel targets for therapeutic interventions. In the present study, we identified increased expression of the mechanosensitive calcium channel Piezo 1 transcripts in mouse and human atherosclerosis, driven by infiltration of PIEZO1-expressing macrophages. We pharmacologically activated or inhibited PIEZO1 both in vitro and in vivo to investigate its role in atherosclerosis. In vitro administration of Yoda1, a PIEZO1 specific agonist, increased foam cell apoptosis and enhanced phagocytosis by macrophages. Mechanistically, we found 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, Yoda1 treated ApoE−/− mice showed regression of atherosclerosis, enhanced plaque stability in advanced lesions, reduced plaque size and necrotic core, increased collagen content, coupled with reduced expression levels of inflammatory markers. Our data suggest that the Ca2+-permeable channel PIEZO1 is a novel and promising therapeutic target to enhance macrophage functions towards atherosclerosis treatment.