Abstract 4366121: Interleukin-6 Neutralization in Pulmonary Arterial Hypertension: Emerging Therapeutic Potential

Introduction: Pulmonary arterial hypertension (PAH) is a progressive and potentially fatal condition characterized by the continuous obstruction of the pulmonary arteries, which ultimately leads to right ventricular (RV) failure. Inflammation plays a crucial role in the development of PAH, with interleukin-6 (IL-6) contributing to vascular remodeling, the proliferation of smooth muscle cells, and fibrosis. Current therapeutic approaches for PAH primarily focus on promoting vasodilation. However, targeting inflammatory mechanisms could serve as a complementary strategy to improve treatment outcomes Hypothesis: We hypothesized that neutralizing IL-6 with species-specific antibodies inhibits the features of PAH in animal models. Methods: Rats in the monocrotaline and sugen/hypoxia mouse model were treated with IL-6 neutralizing antibodies (nAb). After the IL-6 nAb treatment, assessments were conducted that included cardiac magnetic resonance imaging (cMRI) to evaluate RV structure and function, hemodynamic measurements, and histological analyses of lung tissues. Western blotting was performed to assess IL-6/STAT3 and downstream signaling, while transcriptomic changes were analyzed using bulk RNA sequencing. Additionally, the findings were further evaluated in human primary endothelial cells. Results: IL-6 neutralizing antibody (nAb) treatment led to significant improvements in right ventricular (RV) structure and function, as demonstrated by cardiac MRI. Hemodynamic analyses revealed reductions in RV systolic pressure (RVSP) and mean pulmonary arterial pressure (mPAP). Histological evaluations showed a decrease in smooth muscle proliferation and cardiomyocyte hypertrophy. Additionally, IL-6/STAT3 and FOXO downstream signaling were reduced, as indicated by Western blot analysis. The downregulation of genes related to hypertrophy, fibrosis, inflammation, and oxidative stress was further confirmed through RNA sequencing. Conclusion: These findings support the potential of IL-6-targeted therapies as a complementary therapy for PAH. Keywords: Pulmonary arterial hypertension, IL-6, STAT3, IL-6 neutralizing antibody, rodent models.