Published January 21, 2022
| Version v1
Journal article
Open
Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo
Creators
- 1. National Taiwan University
- 2. University of Chicago
- 3. https://orcid.org/0000-0001-8360-9994
- 4. Georgia Institute of Technology
- 5. Veteran General Hospital
- 6. Hospital General Universitario de Castellón
Description
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.
Data availability
All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.Files
sciadv.abl8096.pdf
Files
(10.1 MB)
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Additional details
Identifiers
- DOI
- 10.1126/sciadv.abl8096
- Other
- oai:uchicago.tind.io:10955
Funding
- National Institutes of Health
- R01HL138223
- National Institutes of Health
- R01HL136765
- American Heart Association
- 20TPA35490401
- University of South Alabama
- Chicago Biomedical Consortium
- A-014
- National Taiwan University Hospital
- NTUH.107-T02
- National Taiwan University Hospital
- UN107-019
- National Taiwan University Hospital
- 107-N4062
- National Taiwan University Hospital
- VN107-03
- National Taiwan University Hospital
- 108-T16
- National Taiwan University Hospital
- VN108-06
- National Taiwan University Hospital
- VN109-07
- National Taiwan University Hospital
- VN110-01
- National Taiwan University Hospital
- NTUH.108-P04
- National Taiwan University Hospital
- 108-N4198
- National Taiwan University Hospital
- 108-S4247
- National Taiwan University Hospital
- 108- EDN03
- National Taiwan University Hospital
- 109-EDN05
- National Taiwan University Hospital
- 109-S4576
- National Taiwan University Hospital
- 110-S4836
- National Taiwan University Hospital
- 110-T16
- National Taiwan University
- 109L7872
- Taiwan Ministry of Science Technology
- 108-2314-B-002-199-MY3
- Taiwan Ministry of Science Technology
- 109-2628-B-002-032
- Taiwan National Health Research Institute
- Taiwan National Health Research Institute
- National Taiwan University College of Medicine and National Taiwan University Hospital
- NSCCMOH-131-41
- National Taiwan University College of Medicine and National Taiwan University Hospital
- 109C101-41
- National Taiwan University College of Medicine and National Taiwan University Hospital
- 110C101-071
- Institute of Biomedical Sciences, Academia Sinica
- IBMS-CRC108-P03
- Institute of Biomedical Sciences, Academia Sinica
- AS-TM-109-01-04