Document Type
Article
Publication Date
9-21-2025
Publisher
American Society for Clinical Investigation
Abstract
Pulmonary veno-occlusive disease (PVOD) is a rare and severe subtype of pulmonary arterial hypertension, characterized by progressive remodeling of small pulmonary arteries and veins with no therapies. Using a mitomycin C–induced (MMC-induced) rat model, we previously demonstrated that protein kinase R–mediated (PKR-mediated) integrated stress response (ISR) drives endothelial dysfunction and vascular remodeling. To determine whether PKR is the primary mediator of ISR and the pathogenesis, we treated control (Ctrl) and PKR-knockout (KO) mice with the same dose of MMC. Consistent with rat data, Ctrl mice displayed ISR activation, vascular remodeling, and pulmonary hypertension after MMC treatment, while KO mice showed none of these phenotypes. Proteomic analysis revealed that MMC-mediated ISR activation attenuated protein synthesis in Ctrl but not in KO mice. These findings underscore the critical role of PKR-dependent ISR activation and subsequent perturbation of proteostasis as central mechanisms driving PVOD pathogenesis and identify PKR as a promising therapeutic target.
Recommended Citation
Prabhakar, A., Kumar, R., Wadhwa, M., Barpanda, A., Lyons, J., Gowda, A., Gupta, S., Arvind, A., Ghatpande, P., Wiita, A. P., Graham, B. B., Lagna, G., & Hata, A. (2025). Essential role of protein kinase R in the pathogenesis of pulmonary veno-occlusive disease. JCI Insight, 10(19). https://doi.org/10.1172/jci.insight.193495
Comments
Copyright: © 2025, Prabhakar et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0. International License.