S100A9 promotes pulmonary arterial hypertension by regulating mitochondria–endoplasmic reticulum interaction‐mediated inflammatory injury of endothelial cells

Abstract Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by pulmonary vasoconstriction and remodeling. This study seeks to delineate the role of macrophage‐derived S100 calcium‐binding protein A9 (S100A9) in inducing inflammatory responses mediated by mitochondria‐endoplasmic reticulum (ER) interactions in pulmonary arterial endothelial cells (ECs) during PAH pathogenesis. Both in vivo and in vitro findings consistently revealed that macrophage‐derived S100A9 significantly exacerbated EC injury. Either deletion of S100a9 gene or S100A9 inhibitor restricted pathological progression in PAH mice significantly. S100A9 activates the toll‐like receptor 4 (TLR4)/p38 mitogen‐activated protein kinase (TLR4/p38) pathway in ECs, leading to upregulation of signal‐transducing adaptor protein 2 (STAP2), which subsequently interacts with leucine‐rich repeat kinase 2 to enhance ER‐mitochondrial contact, thereby activating the NOD‐like receptor family pyrin domain containing 3 inflammasome signaling cascade. Targeting STAP2 or inhibiting mitochondria‐ER contact effectively alleviated S100A9‐induced EC injury and PAH progression. This study demonstrates that macrophage‐derived S100A9 promotes pulmonary arterial EC injury via TLR4/STAP2‐mediated mitochondrial–ER interactions, thereby exacerbating PAH progression. Genetic or molecular interventions targeting S100A9 exhibit promising therapeutic potential for ameliorating PAH.