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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Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo
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All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.
Funding Information
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
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