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.
