Wnt/β-catenin signaling in hypoxia-induced pulmonary artery smooth muscle cell proliferation - Role of bioactive molecule of Mucuna pruriens

Abstract

Introduction: Pulmonary hypertension (PH) is a progressive, life-threatening disease characterized by vascular remodeling, constriction, and thrombosis, primarily driven by excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). Hypoxia is a key trigger in PH pathogenesis. The Wnt/β-catenin signaling pathway, critical for cell fate, migration, and organogenesis, plays a pivotal role in PH, with β- catenin mediating transcriptional activation of target genes upon Wnt ligand stimulation. Targeting Wnt/β-catenin signaling represents a promising therapeutic strategy for PH. This study examines its role in hypoxia-exposed PASMCs and evaluates the therapeutic potential of gallic acid and β-sitosterol through in-silico and in-vitro approaches. Objective: To study the role of isolated biomolecules from Mucuna pruriens gallic acid and β-sitosterol on Wnt/ β-catenin mRNA expression in the human pulmonary artery smooth muscle cells exposed to hypoxia. Method: The current study used a computational method based on the ligand-protein interaction technique to determine the therapeutic potential of gallic acid and β- sitosterol with the Wnt/ β catenin pathway. The same compounds are used to investigate. The Invitro study explored the role of gallic acid and β-sitosterol in hypoxia-exposed PASMC lines. Result and Discussion: The current study identified different pharmacological properties of gallic acid and β-sitosterol bioactive molecules to analyze the in silicoADME/T properties. All were within Lipinski’s rule acceptable range, and molecular docking analysis showed that β-sitosterol has more interaction sites with Wnt5a. The Invitro study revealed that when HPASMC is exposed to hypoxia, there is downregulation of the Wnt5a gene and upregulation of the β-catenin gene. β-sitosterol and gallic acid can be attributed to inhibiting the β-catenin pathway via the downregulation of β-catenin gene expression. Conclusion: The present study focused on in-silico phytochemical analysis and in vitro investigations to evaluate the potential therapeutic role of isolated biomolecules from Mucuna pruriens seed extract β-sitosterol and gallic acid in hypoxia-exposed pulmonary artery smooth muscle cells (HPASMCs). These findings suggest that Mucuna pruriens, or its bioactive molecule gallic acid and β-sitosterol, may exert protective effects against hypoxia-induced vascular remodeling by targeting the Wnt/β-catenin signaling pathway.