PIEZO1 targeting in macrophages boosts phagocytic activity and foam cell apoptosis in atherosclerosis
Shirin Pourteymour, Jingxue Fan, Rakesh Kumar Majhi, Shuyuan Guo, Xin Sun, Zhen Huang, Ying Liu, Hanna Winter, Alexandra Bäcklund, Nikolaos-Taxiarchis Skenteris, Ekaterina Chernogubova, Olivera Werngren, Zhaolong Li, Josefin Skogsberg, Yuhuang Li, Ljubica Matic, Ulf Hedin, Lars Mäegdefessel, Ewa Ehrenborg, Ye Tian, Hong Jin
Abstract
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.