Míriam Peracaula, Daniel Aguilar, Àngela Vea, Cristina Rodríguez, Miquel Gratacós-Aurich, Júlia Cabrera-Serra, Jeisson Osorio, Isabel Blanco, Victor I Peinado, Joan Carles Garcia-Pagan, Héctor García Calderó, Virginia Hernández Gea, Ana Paula Dantas, Maribel Diaz-Ricart, Fatima Crispi, Joan Albert Barberà, Olga Tura-Ceide
Dysregulated protein biosynthesis is a characteristic feature of CTEPH, distinguishing them from PAH. Our findings highlight a coordinated translation-mitochondria-MAM axis potentially involved in endothelial dysfunction and vascular remodelling, supporting the need for therapies targeting disease-specific molecular pathways beyond soluble guanylate cyclase stimulation.
OBJECTIVES: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are rare, severe forms of pulmonary hypertension (PH) characterized by elevated mean pulmonary arterial pressure (mPAP) and ∼20% mortality at 3 years. PAH is defined by progressive obliterative vasculopathy, whereas CTEPH results from persistent pulmonary artery obstruction by fibrotic thrombotic material, leading to vascular remodelling, right ventricular hypertrophy, and heart failure.
METHODS: Endothelial colony-forming cells (ECFCs) derived from PAH and CTEPH patients and healthy-controls were analysed to identify disease-specific molecular and functional alterations. Transcriptomic profiling was integrated with functional assays, including global protein synthesis, mitochondrial bioenergetics, intracellular Ca2+ dynamics, and cellular ultrastructural assessment by transmission electron microscopy (TEM). The effects of riociguat, the approved therapy for inoperable or persistent post-surgical CTEPH, were also evaluated.
RESULTS: Significant differences in gene expression profiles were observed among PAH-ECFCs, CTEPH-ECFCs, and control-ECFCs. CTEPH-ECFCs, exhibited a unique upregulation of ribosomal and translation-related genes, accompanied by increased global protein synthesis. Network analysis revealed a highly connected ribosomal-translational hub within CTEPH transcriptome signature. CTEPH-ECFCs also exhibited mitochondrial remodelling, increased endoplasmic reticulum-mitochondria contacts, altered intracellular Ca2+ handling, and reduced maximal respiratory capacity. Riociguat did not reverse these abnormalities.
CONCLUSIONS: Dysregulated protein biosynthesis is a characteristic feature of CTEPH, distinguishing them from PAH. Our findings highlight a coordinated translation-mitochondria-MAM axis potentially involved in endothelial dysfunction and vascular remodelling, supporting the need for therapies targeting disease-specific molecular pathways beyond soluble guanylate cyclase stimulation.