Prisco Sasha Z, Eklund Megan, Raveendran Rashmi, Thenappan Thenappan, Prins Kurt W
Lillehei Heart Institute, Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
JACC Basic Transl Sci. 2021 Nov 22;6(11):834-850. doi: 10.1016/j.jacbts.2021.09.004. eCollection 2021 Nov.
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.
小分子抑制无赖氨酸激酶1（WNK1）（WNK463）信号传导可激活单磷酸腺苷激活的蛋白激酶信号传导，并减轻葡萄糖转运蛋白1和4的膜富集，从而减少蛋白质O-连接的N-乙酰葡糖胺化和糖基化。右心室（RV）线粒体富集物的定量蛋白质组学显示，WNK463可防止几种线粒体代谢酶的下调。代谢组学分析表明多个代谢过程得到纠正。在生理上，WNK463可增强RV的收缩和舒张功能，而与肺动脉高压的严重程度无关。低氯血症是肺动脉高压患者中预测WNK1激活的一种情况，与更严重的RV功能障碍相关。这些结果表明，WNK1可能是对抗代谢失调的可药物作用靶点，并可能改善肺动脉高压患者的RV功能和生存率。
