In pulmonary arterial hypertension, the walls of small lung arteries thicken and narrow, making it harder for blood to pass through and forcing the right side of the heart to work harder. Previous studies have linked this remodeling to blood vessel injury, inflammation and platelet activation. Researchers often use monocrotaline, one of a group of naturally occurring toxins called pyrrolizidine alkaloids, to study these changes in animals. People can encounter these alkaloids in contaminated foods and some herbal products. Which proteins the reactive metabolites bind to, and how those interactions connect platelet activation to arterial wall thickening, have remained open questions.
A study (DOI: 10.48130/targetome-0026-0048) published in Targetome on 23 September 2026 by Yisheng He's team, The Chinese University of Hong Kong, reports that a reactive monocrotaline metabolite modified the platelet prostacyclin receptor and lung PTEN, implicating both proteins in toxin-driven changes to the pulmonary arteries.
The researchers followed rats for four weeks after monocrotaline exposure, collecting blood and lung tissue at intervals and using microscopy to track changes in platelets and pulmonary arteries. Platelets developed features of activation, the arterial walls thickened, and the pressure generated by the heart's right ventricle rose. The team used mass spectrometry to screen for proteins chemically modified by the reactive metabolite, then combined computer modeling with targeted mass spectrometry to pinpoint where it attached. In rat platelets, they detected a modification at histidine 266 of the prostacyclin receptor. The platelets also had lower levels of cyclic AMP, a signaling molecule that helps keep them inactive. In lung tissue, the team detected modifications at several sites on PTEN, including lysine 125. To test whether stimulating the prostacyclin receptor could limit vascular changes, the researchers gave exposed rats selexipag. Treated rats showed less arterial wall thickening, less accumulation of platelet-derived growth factor B in the lungs, and fewer proliferating cells in the arterial walls. In a separate experiment, the team grew rat pulmonary artery smooth muscle cells alongside platelets and exposed the cultures to a reactive form of monocrotaline. Levels of a platelet activation marker and platelet-derived growth factor rose, and the smooth muscle cells multiplied more rapidly. The active metabolite of selexipag reduced those responses and dampened signaling through the growth factor receptor and its downstream pathway. In another group of rats, the researchers used rosiglitazone to increase PTEN levels. That intervention also reduced growth-promoting signaling and arterial wall thickening. Both drug treatments in rats began immediately after toxin exposure, so the experiments measured their effects on the development of vascular damage.
Together, the findings suggest that the toxin may promote arterial thickening in two ways. Activated platelets can supply signals that encourage nearby cells to multiply, while changes to PTEN may weaken the lung's ability to restrain that growth. Further studies will need to determine how much each protein modification contributes to the disease and whether the same changes occur in people exposed to pyrrolizidine alkaloids.
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References
DOI
10.48130/targetome-0026-0048
Original Source URL
https://doi.org/10.48130/targetome-0026-0048
Funding information
This work was supported by the National Natural Science Foundation of China (No. 82474179), the Guangdong Basic and Applied Basic Research Foundation (No. 2024A1515011705, 2023A1515110677), the Foundation of Shenzhen Science and Technology Innovation Commission (No. JCYJ20240813113552066), and the Hospital University United Fund of The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen (HUUF-MS-202301).
About Targetome
Targetome refers to the complete collection of molecular targets (e.g., proteins, RNA or DNA) that interact with and mediate the effect of a specific biomolecule, such as a drug, toxin, metabolites, transcription factor or microRNA, within a biological system. Targetome (Print ISSN 3071-0596; e-ISSN 3070-3808) is an open access journal publishing rigorously peer-reviewed original research articles, reviews, break-through methods, and perspectives that advance our understanding, identification and validation of molecular targets for new drug development.