Endothelial ADAR1 Deficit Induces the NOCT-IRF7 Axis in Pulmonary Hypertension

Area of Science:

• Molecular Biology
• Cell Biology
• Pulmonary Medicine

Background:

• Pulmonary hypertension (PH) involves early apoptosis of pulmonary artery endothelial cells (PAECs), but its regulation is unclear.
• Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA editing enzyme involved in RNA metabolism and apoptosis.
• The specific ADAR1 RNA editing targets and mechanisms controlling PAEC survival in PH remain unknown.

Purpose of the Study:

• To define ADAR1-dependent RNA editing functions and targets in pulmonary endothelial cells.
• To elucidate the mechanisms regulating PAEC survival and pathophenotypes in PH.

Main Methods:

• Evaluated ADAR1 and Nocturnin (NOCT) expression and RNA editing in human PAH lungs and mouse models.
• Utilized in vitro PAEC models under hypoxia and in vivo PH models with genetic manipulations and viral gene delivery.

Main Results:

• ADAR1 expression and global RNA editing were decreased in human and mouse PH lungs.
• Hypoxia downregulated ADAR1 in PAECs, leading to increased NOCT expression and subsequent interferon signaling activation and PAEC apoptosis.
• Silencing NOCT reversed these effects, while forced NOCT expression mimicked ADAR1 knockdown.
• Genetic deletion of NOCT mitigated PH in mice, and ADAR1 expression improved PH in rats.

Conclusions:

• Hypoxia-induced ADAR1 deficiency upregulates NOCT, activating PAEC interferon signaling, promoting apoptosis, and driving PH pathogenesis.
• The ADAR1-NOCT axis represents a potential therapeutic target for PH diagnostics and treatments.