Abstract |
Although atherosclerosis preferentially develops at arterial curvatures and bifurcations where disturbed flow (DF) activates endothelium, therapies targeting flow-dependent mechanosensing pathways in the vasculature are unavailable. Here, we provided experimental evidence demonstrating a previously unidentified causal role of DF-induced endothelial TXNDC5 ( thioredoxin domain containing 5) in atherosclerosis. TXNDC5 was increased in human and mouse atherosclerotic lesions and induced in endothelium subjected to DF. Endothelium-specific Txndc5 deletion markedly reduced atherosclerosis in ApoE-/- mice. Mechanistically, DF-induced TXNDC5 increases proteasome-mediated degradation of heat shock factor 1, leading to reduced heat shock protein 90 and accelerated eNOS ( endothelial nitric oxide synthase) protein degradation. Moreover, nanoparticles formulated to deliver Txndc5-targeting CRISPR-Cas9 plasmids driven by an endothelium-specific promoter (CDH5) significantly increase eNOS protein and reduce atherosclerosis in ApoE-/- mice. These results delineate a new molecular paradigm that DF-induced endothelial TXNDC5 promotes atherosclerosis and establish a proof of concept of targeting endothelial mechanosensitive pathways in vivo against atherosclerosis.
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Authors | Chih-Fan Yeh, Shih-Hsin Cheng, Yu-Shan Lin, Tzu-Pin Shentu, Ru-Ting Huang, Jiayu Zhu, Yen-Ting Chen, Sandeep Kumar, Mao-Shin Lin, Hsien-Li Kao, Po-Hsun Huang, Esther Roselló-Sastre, Francisca Garcia, Hanjoong Jo, Yun Fang, Kai-Chien Yang |
Journal | Science advances
(Sci Adv)
Vol. 8
Issue 3
Pg. eabl8096
(Jan 21 2022)
ISSN: 2375-2548 [Electronic] United States |
PMID | 35061532
(Publication Type: Journal Article)
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