Document Type
Article
Publication Date
11-20-2025
Publisher
American Society for Clinical Investigation
Abstract
To the Editor: Pulmonary veno-occlusive disease (PVOD) is a rare, severe group 1 pulmonary arterial hypertension (PAH) subtype with poor survival (1). PAH-targeted vasodilators can cause life-threatening pulmonary edema in PVOD, underscoring the need for diagnostic tools to distinguish it from other PAH subtypes (1). In patients and mitomycin C–induced (MMC-induced) model animals, aberrant activation of integrated stress response (ISR) via protein kinase R (PKR) drives cardiovascular phenotypes of PVOD (2–4). Inhibition of the PKR-ISR axis, using either the PKR inhibitor C16 or the ISR inhibitor ISRIB, reverses PVOD phenotypes (2–4). Because GDF15 is a cytokine induced by the ISR (5), we compared plasma GDF15 levels in rat models of PVOD and PAH to evaluate its potential as a biomarker. Upon MMC treatment, GDF15 mRNA and plasma protein levels increased (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/JCI199159DS1), and ISRIB reversed treatment reserved this effect (6) (Supplemental Figure 1B). Plasma GDF15 levels were 2.2-fold higher in PVOD model rats compared with those in monocrotaline-induced PAH model rats (Supplemental Figure 1C), suggesting a potential distinction in circulating GDF15 levels between PVOD and other PAH subtypes.
Recommended Citation
Prabhakar, A., Bie, E. M. D. D. D., DesJardin, J. T., Ghatpande, P., Gräf, S., Howard, L. S., Wort, S. J., Church, C., Kiely, D. G., Sumpena, E., Aung, T., Carter, S., Kukreja, J., Hays, S., Greenland, J. R., Singer, J. P., Wax, M., Wolters, P. J., Simon, M. A., … Hata, A. (2026). GDF15 is a putative biomarker for distinguishing pulmonary veno-occlusive disease and pulmonary arterial hypertension. The Journal of Clinical Investigation, 136(2). https://doi.org/10.1172/JCI199159
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.