LINC00599 Promotes Pulmonary Hypertension via Liquid-Liquid Phase Separation With G3BP1 and MYH9

Area of Science:

• Molecular Biology
• Cardiovascular Research
• RNA Biology

Background:

• Pulmonary hypertension (PH) involves vascular remodeling and cell proliferation.
• Long noncoding RNAs (lncRNAs) are implicated in PH pathogenesis, but their precise mechanisms remain unclear.
• Understanding lncRNA interactions is crucial for PH treatment strategies.

Purpose of the Study:

• To investigate the role of LINC00599 in pulmonary hypertension (PH) progression.
• To elucidate the molecular mechanisms by which LINC00599 influences pulmonary arterial smooth muscle cell (PASMC) proliferation.
• To explore LINC00599 as a potential therapeutic target for PH.

Main Methods:

• Quantified LINC00599 expression in mouse lung tissues and hypoxic PASMCs.
• Evaluated LINC00599's role in PH and vascular remodeling using in vivo studies.
• Utilized small interfering RNA and overexpression plasmids to study LINC00599 in human PASMC proliferation.

Main Results:

• LINC00599 expression is upregulated in experimental PH models and hypoxic PASMCs.
• LINC00599 knockdown reversed PH in murine models.
• LINC00599 promotes PASMC proliferation via m6A modification, stress granule formation, and MYH9-mediated liquid-liquid phase separation, driven by ZNF263.

Conclusions:

• LINC00599 promotes PH progression by enhancing PASMC proliferation through a unique liquid-liquid phase separation mechanism.
• LINC00599 modulates m6A-dependent stress granules and MYH9 phase separation, expanding knowledge of lncRNA functions in vascular disease.
• LINC00599 represents a druggable target with potential for PH precision medicine.