A Specific tRNA Half, 3' tiRNA ‐ GlyGCC , Regulates Hypoxic Pulmonary Artery Smooth Muscle Cell Proliferation via Myrf‐Mediated Endoplasmic Reticulum Stress

Pulmonary artery smooth muscle cell (PASMC) proliferation is a hallmark of the pathogenesis of hypoxic pulmonary hypertension (PH), and endoplasmic reticulum stress (ERS) plays a crucial role. Many studies have implicated that tRNA-derived fragment, tiRNAs, in a variety of biological processes, but their roles in hypoxia-induced PASMC ERS and proliferation have not been investigated. In this study, we identified a significantly upregulated 3'tiRNA-GlyGCC in hypoxic mouse lung tissues using Arraystar small RNA microarray analysis. Functional assays, including CCK8, EdU incorporation, Western blot, and immunofluorescence, demonstrated that inhibition of 3'tiRNA-GlyGCC reversed hypoxia-induced ERS and proliferation in PASMCs. Mechanistically, 3'tiRNA-GlyGCC interacts with the eukaryotic translation elongation factor 1 alpha 1 (Eef1a1) protein and reduces the binding capacity between Eef1a1 and myelin regulatory factor (Myrf) mRNA, leading to decreased stability of Myrf mRNA. Additionally, 3'tiRNA-GlyGCC targets Myrf mRNA and inhibits its expression. We further verified that angiogenin (Ang) mediated the biogenesis of 3'tiRNA-GlyGCC under hypoxic conditions. Collectively, these findings highlight a novel mechanism underlying PASMC ERS and proliferation and suggest that 3'tiRNA-GlyGCC could serve as a potential therapeutic target for hypoxic PH.