Nicotine Induces Pyroptosis in Mouse Primary Pulmonary Arterial Endothelial Cells through C x 43-Mediated Activation of the NLRP3/Caspase-1/GSDMD Signaling Pathway

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Abstract Pulmonary arterial hypertension (PAH) is a progressive and life-threatening cardiovascular disorder characterized by pulmonary vascular remodeling, which is closely associated with pyroptosis of pulmonary arterial endothelial cells (PAECs). This study aimed to investigate whether nicotine induces pyroptosis in PAECs by regulating connexin 43 (Cx43) to activate the NLRP3/Caspase-1/GSDMD signaling pathway, thereby contributing to the pathogenesis of PAH. A nicotine-induced PAH model was established in C57BL/6J mice via intranasal instillation. Primary mouse PAECs were isolated and cultured for in vitro studies. Pulmonary vascular remodeling was evaluated using hemodynamic analyses and histopathological staining. RT-qPCR, Western blot, and immunofluorescence were performed to assess Cx43 expression and the activation of the NLRP3/Caspase-1/GSDMD pathway in PAECs. Furthermore, endothelial-cell-specific Cx43 conditional knockdown mice were employed to validate the essential role of Cx43 in this process. We found that nicotine dose-dependently increased right ventricular systolic pressure and induced pulmonary vascular remodeling in mice, accompanied by upregulated Cx43 expression in PAECs. Furthermore, nicotine-induced Cx43 upregulation enhanced the expression of NLRP3, ASC, Caspase-1, and GSDMD. Nicotine also promoted NLRP3 inflammasome assembly, GSDMD cleavage, secretion of IL-1β and IL-18, and LDH release, ultimately leading to pyroptosis in PAECs. Notably, endothelial-cell-specific Cx43 knockdown significantly inhibited nicotine-induced activation of the NLRP3/Caspase-1/GSDMD pathway and attenuated downstream pyroptotic phenotypes in PAECs. Collectively, Cx43 acts as a partial mediator in nicotine-induced PAEC pyroptosis. Nicotine-mediated Cx43 upregulation largely contributes to the activation of the NLRP3/Caspase-1/GSDMD signaling pathway, thereby facilitating pulmonary vascular remodeling and PAH progression. These findings suggest that Cx43 may partially mediate nicotine-induced PAEC pyroptosis and PAH progression and may serve as a novel potential therapeutic target for PAH.

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