Why the study?
Does WNK1 inhibition improve metabolic dysregulation and right ventricular function in pulmonary arterial hypertension?
Does WNK1 inhibition improve metabolic dysregulation and right ventricular function in pulmonary arterial hypertension?
WNK1 inhibition represents a potential novel therapeutic strategy to combat metabolic dysregulation and improve right ventricular function in pulmonary arterial hypertension.
May support WNK1 inhibition for RV function in PAH; leaves open clinical outcome confirmation in larger trials.
Small molecule inhibition of with no lysine kinase 1 (WNK1) (WNK463) signaling activates adenosine monophosphate-activated protein kinase signaling and mitigates membrane enrichment of glucose transporters 1 and 4, which decreases protein O-GlcNAcylation and glycation. Quantitative proteomics of right ventricular (RV) mitochondrial enrichments shows WNK463 prevents down-regulation of several mitochondrial metabolic enzymes. and metabolomics analysis suggests multiple metabolic processes are corrected. Physiologically, WNK463 augments RV systolic and diastolic function independent of pulmonary arterial hypertension severity. Hypochloremia, a condition of predicted WNK1 activation in patients with pulmonary arterial hypertension, is associated with more severe RV dysfunction. These results suggest WNK1 may be a druggable target to combat metabolic dysregulation and may improve RV function and survival in pulmonary arterial hypertension.
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Prisco et al. (2021) studied this question.
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