S100A9 Inhibition Mediates Aerobic Exercise Benefits in Pulmonary Hypertension

BACKGROUND: Previous research has highlighted aerobic exercise as beneficial for patients with pulmonary hypertension (PH) and it is often recommended as a key therapeutic approach. However, the specific mechanisms behind these benefits are not yet fully understood. METHODS: A murine model of hypoxia-induced PH was developed, and the mice underwent 4 weeks of exercise training. The underlying mechanisms were elucidated by utilizing transcriptomic sequencing, in situ immunofluorescence, flow cytometry, cell culture, in vivo mouse experiments, and clinical cohort. RESULTS: Aerobic exercise effectively improved hypoxia-induced pulmonary vascular and right ventricular remodeling. Transcriptomic profiling revealed a marked suppression of inflammatory pathways, with S100A9 identified as the most significantly regulated factor. Under physiological conditions, S100A9 expression is minimal and largely restricted to lung neutrophils; however, hypoxia induces its robust upregulation and widespread distribution, while remaining predominantly neutrophil-associated. Elevated S100A9 promoted immune cell recruitment and impaired pulmonary artery smooth muscle cell function via activation of the TLR4-MyD88-ERK signaling pathway, whereas pharmacological inhibition of S100A9 reduced immune infiltration and restored pulmonary artery smooth muscle cell function. Furthermore, increased S100A9 expression was validated in pulmonary fibrosis-induced PH and in patients with chronic obstructive pulmonary disease associated with PH. The benefits of aerobic exercise in chronic obstructive pulmonary disease associated with PH may be mediated by S100A9 downregulation. CONCLUSIONS: These findings suggest that aerobic exercise alleviates PH by suppressing S100A9-mediated inflammation and vascular remodeling, identifying S100A9 as a biomarker and therapeutic target, and supporting combined exercise rehabilitation and S100A9-targeted therapy for group 3 PH.