Mechanism of IH promoting pulmonary arterial hypertension through ROS-NLRP3 inflammasome mediated endothelial cell pyroptosis.

OBJECTIVE

To investigate the mechanism by which Intermittent Hypoxia (IH) promotes Pulmonary Arterial Hypertension (PAH), focusing on ROS-NLRP3 inflammasome-mediated endothelial cell pyroptosis.

METHODS

Human Pulmonary Microvascular Endothelial Cells (HPMECs) and a monocrotaline-induced PAH rat model were exposed to an IH environment. Interventions included the ROS inhibitor N-acetylcysteine (NAC) and the NLRP3 inhibitor MCC950. Assessments measured cell survival, LDH activity, ROS levels, apoptosis, inflammatory cytokines (IL-1β, IL-18), and protein expression of NLRP3 inflammasome components. In rats, hemodynamics, right ventricular hypertrophy, and pulmonary vascular remodeling were evaluated.

RESULTS

IH exposure significantly decreased HPMEC survival and increased LDH activity, ROS levels, apoptosis rate, and the expression of NLRP3, Caspase-1, and ASC proteins. These effects, along with elevated IL-1β and IL-18, were reversed by NAC and MCC950 treatment. In PAH rats, IH exacerbated right ventricular systolic pressure, pulmonary artery pressure, vascular remodeling, and serum inflammatory markers, which were similarly ameliorated by NAC and MCC950.

CONCLUSION

IH promotes the progression of PAH by inducing endothelial cell pyroptosis through the activation of the ROS-NLRP3 inflammasome pathway.