R213G-Mediated Redistribution of EC-SOD Protects Against Sugen-Hypoxia Pulmonary Hypertension in Mice

Daniel Colon Hidalgo, Caitlin V. Lewis, Thi-Tina N. Nguyen, Janelle N. Posey, Samuel D. Burciaga, Nathan Dee, Christina Sul, Julie Harral, David Irwin, Cassidy Delaney, Eva S. Nozik

https://doi.org/10.1002/pul2.70307 

Abstract

Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling that leads to elevated pulmonary artery pressures, and subsequent right ventricular dysfunction. Despite advances in understanding PH pathogenesis, treatment options remain limited, underscoring the need to define novel mechanisms that contribute to disease progression. Inflammation and oxidative stress are recognized drivers of pulmonary vascular injury, with extracellular superoxide dismutase (EC-SOD or SOD3), a matrix-bound antioxidant enzyme, playing a role in multiple lung and vascular pathologies. A common human single nucleotide polymorphism (rs1799895) in the SOD3 gene leads to an arginine to glycine amino acid substitution (R213G) and alters EC-SOD localization by reducing its affinity for the extracellular matrix, resulting in increased circulating but decreased lung EC-SOD content. Using a murine knock-in model of the R213G variant, we have previously demonstrated exacerbated chronic hypoxia-induced PH. In this study, we examined the impact of EC-SOD redistribution due to the R213G SOD3 variant on the development of PH in the Sugen-hypoxia (SuHx) model, a more severe model of PH. We hypothesized that R213G mice would also have exaggerated hemodynamic changes, vascular remodeling, and inflammatory changes in this model. However, while SuHx increased pulmonary artery pressure and vascular remodeling in wild-type mice, the R213G variant unexpectedly attenuated SuHx-induced PH. Following SuHx, the increase in pulmonary artery pressures was attenuated in R213G mice. Early immune profiling revealed that SuHx triggered significant neutrophil and interstitial macrophage infiltration in the lungs of wild-type mice, which was markedly blunted in R213G mice. These findings suggest that the redistribution of EC-SOD into the extracellular fluid, though it lowed lung EC-SOD levels, attenuated early inflammatory responses and protected against the development of PH in SuHx. This work highlights a novel, compartment-specific role for EC-SOD in modulating immune-driven mechanisms of PH and may inform future therapeutic strategies targeting oxidative stress and inflammation in vascular disease.

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