KRIT1 Inhibits TGF-β/Smad-Mediated Endothelial-To-Mesenchymal Transition in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is characterized by pulmonary endothelial cell (EC) dysfunction and pulmonary vascular remodelling. Endothelial-to-mesenchymal transition (EndMT) is a key mechanism underlying pulmonary vascular remodelling. Krev interaction trapped protein 1 (KRIT1) plays a crucial role in maintaining vascular endothelial stability, but its association with PAH remains unclear. Analysis of RNA expression microarray data from the GEO database revealed that KRIT1 expression was downregulated in the lung tissues of PAH patients. In the monocrotaline (MCT)-induced PAH rat model, KRIT1 expression in lung tissue was reduced, accompanied by typical PAH phenotypes, including elevated right ventricular systolic pressure, right ventricular hypertrophy, and increased pulmonary artery wall thickness. In vitro, EndMT in primary rat pulmonary artery ECs (rPAECs) was induced by inflammatory cytokines, and KRIT1 expression was suppressed during this process. Overexpression of KRIT1 attenuated the EndMT-associated molecular phenotype, with increased VE-cadherin and reduced α-SMA expression, and inhibited the enhanced migratory activity of rPAECs. Mechanistically, KRIT1 may exert anti-EndMT effects by negatively regulating the TGF-β/Smad signalling pathway, as evidenced by reduced Smad2/3 phosphorylation. This effect was abrogated by a TGF-β/Smad pathway agonist. In addition, KRIT1 overexpression suppressed β-catenin nuclear translocation. This study reveals a role for KRIT1 in maintaining endothelial homeostasis, suggesting its potential involvement in PAH-associated vascular remodelling.