Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages

Redox Biol. 2023 May:61:102638. doi: 10.1016/j.redox.2023.102638. Epub 2023 Feb 15.

Abstract

Pulmonary hypertension (PH) is a devastating disease characterized by irreversible pulmonary vascular remodeling (PVR) that causes right ventricular failure and death. The early alternative activation of macrophages is a critical event in the development of PVR and PH, but the underlying mechanisms remain elusive. Previously we have shown that N6-methyladenosine (m6A) modifications of RNA contribute to phenotypic switching of pulmonary artery smooth muscle cells and PH. In the current study, we identify Ythdf2, an m6A reader, as an important regulator of pulmonary inflammation and redox regulation in PH. In a mouse model of PH, the protein expression of Ythdf2 was increased in alveolar macrophages (AMs) during the early stages of hypoxia. Mice with a myeloid specific knockout of Ythdf2 (Ythdf2Lyz2 Cre) were protected from PH with attenuated right ventricular hypertrophy and PVR compared to control mice and this was accompanied by decreased macrophage polarization and oxidative stress. In the absence of Ythdf2, heme oxygenase 1 (Hmox1) mRNA and protein expression were significantly elevated in hypoxic AMs. Mechanistically, Ythdf2 promoted the degradation of Hmox1 mRNA in a m6A dependent manner. Furthermore, an inhibitor of Hmox1 promoted macrophage alternative activation, and reversed the protection from PH seen in Ythdf2Lyz2 Cre mice under hypoxic exposure. Together, our data reveal a novel mechanism linking m6A RNA modification with changes in macrophage phenotype, inflammation and oxidative stress in PH, and identify Hmox1 as a downstream target of Ythdf2, suggesting that Ythdf2 may be a therapeutic target in PH.

Keywords: Alveolar macrophages; Heme oxygenase 1; Inflammation; Oxidant stress; Pulmonary hypertension; Ythdf2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents
  • Antioxidants
  • Heme Oxygenase-1 / genetics
  • Hypertension, Pulmonary* / metabolism
  • Hypoxia
  • Macrophages, Alveolar* / metabolism
  • Membrane Proteins
  • Mice
  • RNA
  • RNA, Messenger / metabolism
  • Transcription Factors

Substances

  • Antioxidants
  • Heme Oxygenase-1
  • Transcription Factors
  • Anti-Inflammatory Agents
  • RNA, Messenger
  • RNA
  • Hmox1 protein, mouse
  • Membrane Proteins