Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo

• Type of Material: Article
• Authors: Chih-Fan Yeh, National Taiwan University Hospital; Shih-Hsin Cheng, National Taiwan University College of Medicine; Yu-Shan Lin, National Taiwan University College of Medicine; Tzu-Pin Shentu, University of Chicago; Ru-Ting Huang, University of Chicago; Jiayu Zhu, University of Chicago; Yen-Ting Chen, National Taiwan University College of Medicine; Sandeep Kumar, Emory University; Mao-Shin Lin, National Taiwan University Hospital; Hsien-Li Kao, National Taiwan University Hospital; Po-Hsun Huang, Veteran General Hospital; Esther Roselló-Sastre, Hospital General Universitario de Castellón; Francisca Garcia, Hospital General Universitario de Castellón; Hanjoong Jo, Emory University; Yun Fang, University of Chicago; Kai-Chien Yang, National Taiwan University Hospital
• Language: English
• Date: 2022-01-01
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.abl8096
• Title of Journal or Parent Work: SCIENCE ADVANCES
• Volume: 8
• Issue: 3
• Start Page: eabl8096
• End Page: eabl8096
• Grant/Funding Information: This work was funded by the Taiwan Ministry of Science Technology grants 108-2314-B-002-199-MY3 and 109-2628-B-002-032 (to K.-C.Y.); an Innovative Research Grant from Taiwan National Health Research Institute NHRI-EX109-10936SI (to K.-C.Y.); a CRC Translational Research grant IBMS-CRC108-P03 (to K.-C.Y.) and a Translational Medicine grant AS-TM-109-01-04 (to K.-C.Y.) from the Institute of Biomedical Sciences at Academia Sinica, Taiwan; grants from National Taiwan University Hospital NTUH.107-T02, UN107-019, 107-N4062, VN107-03, 108-T16, VN108-06, VN109-07, VN110-01, NTUH.108-P04, 108-N4198, 108-S4247, 108-EDN03, 109-EDN05, 109-S4576, 110-S4836, and 110-T16 (to K.-C.Y.); grants from the Excellent Translation Medicine Research Projects of National Taiwan University College of Medicine and National Taiwan University Hospital NSCCMOH-131-41, 109C101-41, and 110C101-071 (to K.-C.Y.); and a Career Development Grant from National Taiwan University 109L7872 (to K.-C.Y.); as well as by Chicago Biomedical Consortium A-014; American Heart Association 20TPA35490401 (to Y.F.); and National Institutes of Health/NIH R01HL138223 (to Y.F.), R01HL136765 (to Y.F.), R01HL119798 (to H.J.), and R01HL139757 (to H.J.). These funding agencies had no role in the study design, data collection/analyses, and preparation of the manuscript or decision to publish.
• Keywords: Multidisciplinary Sciences; SHEAR-STRESS; ACTIVATION; NITRIC-OXIDE SYNTHASE; EXPRESSION; GENE DELIVERY; ACCELERATED ATHEROSCLEROSIS; HEAT-SHOCK PROTEINS; Science & Technology - Other Topics; Science & Technology; DISTURBED FLOW; PROTEIN-DISULFIDE-ISOMERASE; KRUPPEL-LIKE FACTOR-2
• Research Categories: Health Sciences, Pathology; Health Sciences, Medicine and Surgery

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.