Reduced CircSMOC1 Level Promotes Metabolic Reprogramming via PTBP1 (Polypyrimidine Tract-Binding Protein) and...

Area of Science:

• Cardiovascular Research
• Molecular Biology
• Cellular Metabolism

Background:

• Pulmonary arterial hypertension (PAH) involves rapid cell proliferation and vascular remodeling driven by metabolic reprogramming.
• Circular RNAs (circRNAs) are implicated in PAH vascular remodeling and smooth muscle cell proliferation.
• The interplay between circRNAs, cell proliferation, and metabolic reprogramming in PAH remains underexplored.

Purpose of the Study:

• To investigate the role of circRNAs in pulmonary arterial hypertension (PAH).
• To elucidate the function of circSMOC1 in regulating pulmonary artery smooth muscle cell proliferation and metabolic reprogramming in PAH.
• To identify the molecular mechanisms by which circSMOC1 influences PAH pathogenesis.

Main Methods:

• Differential expression profiling of circRNAs in PAH rat models using RNA-sequencing and qRT-PCR.
• In vitro studies involving transfection of circSMOC1 in pulmonary artery smooth muscle cells.
• In vivo validation using adeno-associated virus delivery of circSMOC1.
• Mechanistic investigations including mass spectrometry, RNA pull-down, RNA immunoprecipitation, and dual-luciferase reporter assays.

Main Results:

• CircSMOC1 expression was significantly reduced in pulmonary arteries of PAH rats.
• Knockdown of circSMOC1 promoted pulmonary artery smooth muscle cell proliferation, migration, and aerobic glycolysis.
• Overexpression of circSMOC1 ameliorated pulmonary vascular remodeling, right ventricular pressure, and right heart hypertrophy in vivo.
• CircSMOC1 regulates glycolysis via nuclear interaction with PTBP1 to control PKM splicing and cytoplasmic sponging of miR-329-3p to affect mitochondrial oxidative phosphorylation.

Conclusions:

• CircSMOC1 plays a critical role in the metabolic reprogramming of pulmonary artery smooth muscle cells in PAH.
• CircSMOC1 modulates pulmonary vascular remodeling through interactions with PTBP1 and miR-329-3p.
• circSMOC1 represents a potential therapeutic target for pulmonary arterial hypertension.