Abstract 11698: Pulmonary Hypertension in S100A1 KO Mice is Associated With Endothelial Cell Dysfunction and Impaired eNOS Activation Dependent in Part on the Receptor for Advanced Glycation End-Products (RAGE)

Background: S100A1, a 10-kDa, Ca 2+ - binding protein is expressed in endothelial cells and its absence is associated with impaired production of nitric oxide (NO) and mild systemic hypertension. As endothelial dysfunction contributes to clinical and experimental pulmonary hypertension (PH), we investigated the impact of deleting S100A1 in knockout mice (KO) on pulmonary hemodynamic and endothelial function. Methods and Results: Under basal conditions in vivo, S100A1 deficient mice exhibited a significant elevation in right ventricular systolic pressure (28.41±3.6 vs.14.9±2.41 mmHg in wild-type (WT), p -4 M increased fluorescence 1.43±0.31-fold vs. 3.91±0.43-fold in WT, p 1177 , by exogenous S100A1 treatment (100nM, 30 min) was 2.19- fold greater in WT vs. KO (p Conclusion: Absence of S100A1 results in PH by disrupting its normal capacity to enhance pulmonary endothelial cell function by induction of eNOS activity and NO levels. The ability of exogenously administered S100A1 to rescue this phenotype mediated by RAGE represents a possible therapeutic target in the treatment of PH.