o ⁸ G Site-Specifically Modified tRF-1-AspGTC: A Novel Therapeutic Target and Biomarker for Pulmonary Hypertension

Abstract

RATIONALE: Hypoxia and oxidative stress contribute to the development of pulmonary hypertension (PH). tRNA-derived fragments play important roles in RNA interference and cell proliferation, but their epitranscriptional roles in PH development have not been investigated. OBJECTIVE: We aimed to gain insight into the mechanistic contribution of oxidative stress–induced 8-oxoguanine in pulmonary vascular remodeling. METHODS AND RESULTS: Through small RNA modification array analysis and quantitative polymerase chain reaction, a significant upregulation of the 8-oxoguanine–modified tRF-1-AspGTC was found in the lung tissues and the serum of patients with PH. This modification occurs at the fifth 8-oxoguanine (5o 8 G) tRF in the seed region of the tRNA-derived fragments. Inhibition of the 5o 8 G tRF reversed hypoxia-induced proliferation and apoptosis resistance in pulmonary artery smooth muscle cells. Further investigation unveiled that the 5o 8 G tRF retargeted mRNA of WNT5A and CASP3 and inhibited their expression. Ultimately, BMPR2 (bone morphogenetic protein receptor 2)–reactive oxygen species/5o 8 G tRF/WNT5A signaling pathway exacerbated the progression of PH. CONCLUSIONS: Our study highlights the role of site-specific 8-oxoguanine–modified tRF in promoting the development of PH. Our findings present a promising therapeutic avenue for managing PH and propose 5o 8 G tRF as a potential innovative marker for diagnosing this disease.