A loss-of-function polymorphism in the propeptide of lysyl oxidase exacerbates atherosclerosis.
IH, J., JM, A., SE, L., RE, W., A, A., PC, L., KH, B., J, O., HC, P.P., & CJ, K. (2026). A loss-of-function polymorphism in the propeptide of lysyl oxidase exacerbates atherosclerosis.. JCI insight. https://doi.org/10.1172/jci.insight.201535
IH J, JM A, SE L, RE W, A A, PC L, et al. A loss-of-function polymorphism in the propeptide of lysyl oxidase exacerbates atherosclerosis.. JCI insight. 2026; doi: 10.1172/jci.insight.201535
IH J, JM A, SE L, et al. A loss-of-function polymorphism in the propeptide of lysyl oxidase exacerbates atherosclerosis.[J]. JCI insight. 2026. DOI: 10.1172/jci.insight.201535.
@article{ih2026,
author = {Jung IH and Amrute JM and Luna SE and Wagoner RE and Alisio A and Lee PC and Burks KH and Oh J and Plunkett Paletta HC and Kang CJ},
title = {A loss-of-function polymorphism in the propeptide of lysyl oxidase exacerbates atherosclerosis.},
journal = {JCI insight},
year = {2026},
doi = {10.1172/jci.insight.201535},
note = {PMID: 42484377},
}
TY - JOUR AU - Jung IH AU - Amrute JM AU - Luna SE AU - Wagoner RE AU - Alisio A AU - Lee PC AU - Burks KH AU - Oh J AU - Plunkett Paletta HC AU - Kang CJ TI - A loss-of-function polymorphism in the propeptide of lysyl oxidase exacerbates atherosclerosis. T2 - JCI insight PY - 2026 DO - 10.1172/jci.insight.201535 AN - PMID:42484377 ER -
A single-nucleotide missense polymorphism (rs1800449, R158Q) in the propeptide domain of lysyl oxidase (LOX-PP) is associated with increased risk of coronary artery disease (CAD) independent of changes in plasma lipid levels. Although the enzymatic function of LOX has an essential role for the cross-linking of extracellular matrix proteins in connective tissues, whether and how LOX-PP R158Q contributes to the development of atherosclerosis has not been clearly established. Here, hypercholesterolemia was induced in mice that were WT or homozygous for the LOX-PP R158Q polymorphism by adeno-associated virus-8-mediated overexpression of Pcsk9 followed by high-fat diet feeding for 16 weeks. We found that the R158Q polymorphism promoted atherosclerosis and induced proliferation of macrophages and vascular smooth muscle cells without altering LOX enzymatic activity. Using single-cell RNA sequencing, we found the transcriptional program of atherosclerotic plaques from mice harboring R158Q was strongly enriched for proliferation- and calcification-related genes in a regionally distinct manner. Together, these results establish an enzymatically independent proatherogenic role for the LOX-PP and suggest its potential as a novel therapeutic target.