Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35061532.
- Also identified by DOI 10.1126/sciadv.abl8096 and PMC identifier 8782452.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 <i>Txndc5</i> deletion markedly reduced atherosclerosis in <i>ApoE</i><sup>-/-</sup> 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 <i>Txndc5</i>-targeting CRISPR-Cas9 plasmids driven by an endothelium-specific promoter (<i>CDH5</i>) significantly increase eNOS protein and reduce atherosclerosis in <i>ApoE</i><sup>-/-</sup> 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.