KRIT1 maintains endothelial homeostasis by negatively regulating TGF-β/Smad signalling to inhibit endothelial-to-mesenchymal transition, suggesting its potential involvement in PAH-associated vascular remodelling.
KRIT1 expression was downregulated in lung tissues of PAH patients based on GEO database RNA expression microarray analysis.
KRIT1 expression was reduced in lung tissue of MCT-induced PAH rats, accompanied by hallmark PAH phenotypes.
KRIT1 expression was suppressed during inflammatory cytokine-induced endothelial-to-mesenchymal transition (EndMT) in primary rat pulmonary artery endothelial cells (rPAECs).
Overexpression of KRIT1 attenuated the EndMT-associated molecular phenotype in rPAECs.
KRIT1 exerts anti-EndMT effects by negatively regulating the TGF-β/Smad signalling pathway, as evidenced by reduced Smad2/3 phosphorylation.
KRIT1 overexpression suppressed β-catenin nuclear translocation in rPAECs.
Pulmonary arterial hypertension (PAH) is a serious disease where the blood vessels in the lungs become thickened and narrowed, making it hard for the heart to pump blood. One key process driving this thickening is called endothelial-to-mesenchymal transition (EndMT), where cells lining blood vessels change into a stiffer, scar-like cell type. This research suggests that a protein called KRIT1, known for maintaining blood vessel stability, plays an important protective role against this harmful transformation. The researchers found that KRIT1 levels were lower than normal in lung tissue from PAH patients, in a rat model of PAH, and in lung vessel cells undergoing EndMT in the laboratory. When the researchers artificially increased KRIT1 levels in rat pulmonary artery cells, the cells were better able to resist the EndMT process — they retained more of their normal endothelial identity (higher VE-cadherin) and showed less of the scar-like characteristics (lower α-SMA) associated with disease. They also moved around less, which is another sign of a healthier, more stable cell. Mechanistically, KRIT1 appeared to work by dampening a well-known disease-promoting signalling pathway called TGF-β/Smad, as well as reducing the movement of a molecule called β-catenin into the cell nucleus — both of which drive the harmful cell transformation. This research suggests that the loss of KRIT1 in PAH may leave blood vessel cells vulnerable to disease-driving changes, and that restoring or boosting KRIT1 activity could be a potential avenue for limiting the vascular remodelling that makes PAH so dangerous. While the findings are at an early, preclinical stage, they identify KRIT1 and the TGF-β/Smad pathway as a potential therapeutic target worth further investigation in PAH.
Ma D, Shi L, Li C, Song D, Liu L. (2026). KRIT1 Inhibits TGF-β/Smad-Mediated Endothelial-To-Mesenchymal Transition in Pulmonary Arterial Hypertension.. Clinical and experimental pharmacology & physiology. https://doi.org/10.1111/1440-1681.70161