J Am Heart Assoc. 2026 Aug 7:e045577. doi: 10.1161/JAHA.125.045577. Online ahead of print.
ABSTRACT
BACKGROUND: Pulmonary hypertension is a malignant cardiovascular disease characterized by pulmonary vascular remodeling, with core pathological features including pulmonary arterial wall thickening and elevated pulmonary vascular remodeling due to aberrant proliferation of pulmonary arterial smooth muscle cells (PASMCs). The molecular regulatory mechanisms underlying pulmonary vascular remodeling remain incompletely understood.
METHODS: Transcriptome sequencing was employed to screen for differentially expressed genes in lung artery tissues of control and Sugen5416 combined hypoxia-induced rat models. A series of in vitro and in vivo experiments, including scratch assays, EdU staining, Cell Counting Kit-8cell proliferation assays, immunofluorescence, immunoblotting, and overexpression/knockdown techniques, were performed to investigate the molecular mechanism by which KRT17 (keratin 17) induces PASMCs proliferation and promotes pulmonary hypertension vascular remodeling.
RESULTS: KRT17 was found to be highly expressed in lung tissues of patients with pulmonary hypertension, as well as in pulmonary arterial tissue and hypoxic PASMCs models. Both in vivo and in vitro experiments demonstrated that KRT17 was a critical regulator of PASMCs proliferation. METTL14 (methyltransferasean14, an m6A methyltransferase complex subunit) was identified as a potential modulator of KRT17 RNA methylation, enhancing its RNA stability and protein expression. Furthermore, KRT17 promoted PASMCs proliferation through upregulation of LCN2 (lipocalin-2).
CONCLUSIONS: Our study reveals a novel molecular mechanism by which KRT17 expression is regulated via METTL14-mediated m6A methylation, and further elucidates the role of KRT17 in inducing PASMCs proliferation through the LCN2 signaling pathway. These findings provide significant theoretical insights for the development of innovative therapeutic targets for pulmonary hypertension.
PMID:42568103 | DOI:10.1161/JAHA.125.045577