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Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • NITRIC-OXIDE SYNTHASE
  • KRUPPEL-LIKE FACTOR-2
  • PROTEIN-DISULFIDE-ISOMERASE
  • HEAT-SHOCK PROTEINS
  • SHEAR-STRESS
  • ACCELERATED ATHEROSCLEROSIS
  • DISTURBED FLOW
  • GENE DELIVERY
  • EXPRESSION
  • ACTIVATION

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

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Journal Title:

SCIENCE ADVANCES

Volume:

Volume 8, Number 3

Publisher:

, Pages eabl8096-eabl8096

Type of Work:

Article

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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