o8G Site-Specifically Modified tRF-1-AspGTC: A Novel Therapeutic Target and Biomarker for Pulmonary Hypertension

Circ Res. 2024 Jun 21;135(1):76-92. doi: 10.1161/CIRCRESAHA.124.324421. Epub 2024 May 15.

Abstract

Background: 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. We aimed to gain insight into the mechanistic contribution of oxidative stress-induced 8-oxoguanine in pulmonary vascular remodeling.

Methods: 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.

Results: This modification occurs at the position 5 of the tRF-1-AspGTC (5o8G tRF). Inhibition of the 5o8G tRF reversed hypoxia-induced proliferation and apoptosis resistance in pulmonary artery smooth muscle cells. Further investigation unveiled that the 5o8G tRF retargeted mRNA of WNT5A (Wingless-type MMTV integration site family, member 5A) and CASP3 (Caspase3) and inhibited their expression. Ultimately, BMPR2 (Bone morphogenetic protein receptor 2) -reactive oxygen species/5o8G 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 5o8G tRF as a potential innovative marker for diagnosing this disease.

Keywords: blood pressure; cell proliferation; hypertension; reactive oxygen species; vascular remodeling.

MeSH terms

  • Animals
  • Apoptosis
  • Biomarkers* / blood
  • Biomarkers* / metabolism
  • Bone Morphogenetic Protein Receptors, Type II* / genetics
  • Bone Morphogenetic Protein Receptors, Type II* / metabolism
  • Caspase 3 / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Female
  • Guanine / analogs & derivatives
  • Guanine / metabolism
  • Humans
  • Hypertension, Pulmonary* / etiology
  • Hypertension, Pulmonary* / genetics
  • Hypertension, Pulmonary* / metabolism
  • Male
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle / metabolism
  • Oxidative Stress
  • Pulmonary Artery* / metabolism
  • Rats
  • Reactive Oxygen Species / metabolism
  • Vascular Remodeling
  • Wnt-5a Protein / genetics
  • Wnt-5a Protein / metabolism

Substances

  • Bone Morphogenetic Protein Receptors, Type II
  • Biomarkers
  • BMPR2 protein, human
  • Wnt-5a Protein
  • WNT5A protein, human
  • 8-hydroxyguanine
  • Guanine
  • Caspase 3
  • CASP3 protein, human
  • Reactive Oxygen Species