Megan Eklund

Background: Pulmonary arterial hypertension (PAH) is a fatal disease with a median survival of only 5-7 years. Increased expression of Glut1 and Glut4 occurs in the RV in PAH, but the upstream regulators of these proteins are unknown. The With-no-Lysine (WNK) kinase-1 promotes expression of Glut1/4 in skeletal muscle, but its regulation in the RV in PAH is unexplored. Furthermore, the relationship between WNK1, Glut1, Glut4, and protein O-GlcNACylation (POGN) in the RV are unknown. Methods: Immunoblots and confocal microscopy were used to quantify the abundance and localization of WNK1, Glut1, Glut4, and total POGN in the RV and left ventricle (LV) of the monocrotaline (MCT) and pulmonary artery banded (PAB) rats. Results: WNK1 expression was increased 1.5-fold in MCT RV and 1.2-fold in PAB RV extracts. WNK1 expression was significantly correlated with Glut 1 (r=0.86, p-value=0.006) and Glut 4 (r=0.94, p-value=0.0006) in MCT extracts. In PAB extracts, there were nonsignificant correlations with WNK1 and Glut 1 (r=0.54, p-value=0.14) and Glut 4 (r=0.58, p-value=0.099). Total POGN was significantly associated with WNK1 expression in both MCT (r=0.7, p-value=0.04) and PAB RV (r=0.74, p-value=0.01) extracts. Conclusions: Hypochloremia predicts mortality in PAH. WNK1 expression is increased in RV pressure overload and its expression is highly correlated with Glut 1 and 4 and total POGN. These results may provide new insights into RV dysfunction in PAH.