Narciclasine as a Novel Therapeutic Target for Pulmonary Arterial Hypertension: Addressing Glycosylation in Disease Pathophysiology.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by vasoconstriction and remodeling of pulmonary arteries, leading to increased pressure and right ventricle failure. This condition is associated with transcriptomic changes promoting metabolic disorders, inflammation, and a pro-survival phenotype in pulmonary artery smooth muscle cells (PASMCs). Transcriptomic analysis of PAH patient lung samples identified 4013 differentially expressed genes. Using pharmaco-transcriptomic databases, narciclasine emerged as a promising candidate. Hypothesizing narciclasine could counteract PAH, we administered it in a murine PAH model induced by monocrotaline. Results showed improvements in pulmonary hemodynamics, reduced right ventricular systolic pressure (RVSP), pulmonary artery acceleration time (PAAT), and total pulmonary resistance (TPR). Narciclasine treatment decreased inflammatory markers, PASMC proliferation, and vascular remodeling, promoting apoptosis. In vitro, narciclasine reduced PASMC proliferation and enhanced apoptosis, implicating glycosylation downregulation as its mechanism. This pathogenic factor in PAH was reversed by narciclasine, which also downregulated key glycosylation enzymes (both in vivo and in vitro), introducing a novel therapeutic pathway. Our study suggests that narciclasine may potentially improve PAH by targeting glycosylation. Utilizing a pharmaco-transcriptomic approach, our work indicates that narciclasine can enhance PAH outcomes both in vivo and in vitro.