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

Author:

Pourteymour Shirin,Fan Jingxue,Majhi Rakesh Kumar,Guo Shuyuan,Sun Xin,Huang Zhen,Liu Ying,Winter Hanna,Bäcklund Alexandra,Skenteris Nikolaos-Taxiarchis,Chernogubova Ekaterina,Werngren Olivera,Li Zhaolong,Skogsberg Josefin,Li Yuhuang,Matic Ljubica,Hedin Ulf,Maegdefessel Lars,Ehrenborg Ewa,Tian Ye,Jin HongORCID

Abstract

AbstractThe 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.

Funder

Magnus Bergvalls Foundation

H2020 Marie Skłodowska-Curie Actions

Vetenskapsrådet

Hjärt-Lungfonden

Karolinska Institutet

Stiftelsen för Gamla Tjänarinnor

National Key Scientific Instrument and Equipment Development Projects of China

The State Key Program of the National Science Foundation of China

The Young Scientist Fund of the National Natural Science Foundation of China

Karolinska Institute

Publisher

Springer Science and Business Media LLC

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