Abstract Body (Do not enter title and authors here): Background: Pulmonary arterial hypertension (PAH) is characterized by an elevation in pulmonary vascular resistance and arterial pressure, culminating in right ventricular failure and mortality. Excessive proliferation and accumulation of pulmonary artery smooth muscle cells (PASMCs), driven by aberrant gene expression, stand as hallmark pathologies of PAH. Among the regulatory elements implicated in this process, microRNAs (miRNAs) such as miR-203a-3p are crucial, influencing cellular proliferation and migration. Nevertheless, the precise role and mechanisms through which miR-203a-3p modulates PAH pathophysiology remain poorly defined.
Objective: This study seeks to elucidate the expression patterns and functional roles of miR-203a-3p in idiopathic pulmonary arterial hypertension (IPAH) and in rodent models of PAH, with an emphasis on understanding the underlying molecular mechanisms.
Methods: Expression levels of miR-203a-3p were quantified in plasma from IPAH patients and healthy controls via RT-qPCR at the Second Xiangya Hospital. Rodent models of PAH were generated using either Monocrotaline (MCT) or Su5416 in conjunction with chronic hypoxia. MiR-203a-3p expression in plasma and lung tissue was evaluated at predetermined intervals. Additionally, the effects of miR-203a-3p overexpression on primary PASMC functions were assessed, and therapeutic potential was explored through administration of an adeno-associated virus vector encoding miR-203a-3p prior to model induction.
Results: Significantly reduced levels of miR-203a-3p were observed in both IPAH patients and PAH-model rats compared to healthy controls, correlating inversely with indicators of disease progression. Overexpression of miR-203a-3p inhibited PASMC proliferation and migration and attenuated disease phenotypes in experimental models. Molecular analysis revealed that miR-203a-3p directly targets PIK3CA, influencing the PI3K/Akt signaling pathway, a critical mediator of PASMC function.
Conclusion: The downregulation of miR-203a-3p in IPAH and its regulatory impact on PASMC behavior via the PIK3CA/PI3K/Akt pathway highlight its potential utility as a biomarker and therapeutic target in PAH. These findings provide a foundation for further investigations into the therapeutic benefits of miR-203a-3p in the clinical management of PAH, supporting its development as a novel therapeutic strategy.