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bioRxiv · 10.1101/2021.06.22.449476

With No Lysine Kinase 1 Promotes Right Ventricular Dysfunction Via Glucotoxicity

Prisco, S. Z.·Eklund, M.·Thenappan, T.·Prins, K. W.
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Abstract

ObjectivesInvestigate how WNK1 inhibition modulates glucotoxicity, mitochondrial/peroxisomal protein regulation and metabolism, and right ventricular (RV) function in pulmonary arterial hypertension (PAH). Determine how hypochloremia impacts RV function in PAH patients. BackgroundIn PAH-induced RV failure, GLUT1/GLUT4 expression is elevated, which increases glucose uptake and glycolytic flux to compensate for mitochondrial dysfunction. However, the resultant consequences of the glucose-mediated post-translational modifications (PTM), protein O-GlcNAcylation/glycation in RV failure are understudied. WNK1, a chloride-sensitive kinase, increases GLUT1/GLUT4 expression in skeletal muscle, but its regulation in RV dysfunction is unexplored. MethodsRats were treated with WNK463 (small molecule WNK inhibitor) or vehicle starting two weeks after monocrotaline injection. Immunoblots quantified protein abundance/PTMs. Mitochondrial/peroxisomal proteomics and global metabolomics evaluated glucose metabolism and mitochondrial/peroxisomal function. Pulmonary vascular and cardiac histology, echocardiography, and pressure-volume loop analysis quantified RV function and PAH severity. Finally, the relationship between hypochloremia, a WNK1-activating state, and RV function was evaluated in 217 PAH patients. ResultsWNK463 decreased WNK1/GLUT1/GLUT4 expression, normalized glucose metabolite levels, which dampened excess protein O-GlcNAcylation/glycation. Integration of RV mitochondrial/peroxisomal proteomics and metabolomics identified fatty acid oxidation (FAO) as the most dysregulated metabolic pathway. WNK463 enhanced FAO as demonstrated by increased expression of mitochondrial FAO proteins and normalization of RV acylcarnitines. WNK463 reduced glutaminolysis induction and lipotoxicity, two secondary consequences of diminished FAO. WNK463 augmented RV systolic and diastolic function independent of pulmonary vascular disease severity. In PAH patients, hypochloremia resulted in more severe RV dysfunction. ConclusionsWNK463 combated RV glucotoxicity and impaired FAO, which directly improved RV function. HighlightsO_LISmall molecule inhibition of WNK1 (WNK463) signaling mitigates upregulation of the membrane glucose channels GLUT1 and GLUT4, restores levels of several glucose metabolites, and normalizes protein O-GlcNAcylation and glycation in the RV. C_LIO_LIQuantitative proteomics of RV mitochondrial enrichments shows WNK463 treatment prevents downregulation of mitochondrial enzymes in the tricarboxylic acid cycle, fatty acid oxidation pathway, and the electron transport chain complexes. C_LIO_LIIntegration of proteomics and metabolomics analysis reveals WNK463 reduces glutaminolysis induction and lipotoxicity due to impaired fatty acid oxidation C_LIO_LIWNK463 augments RV systolic and diastolic function independent of PAH severity. C_LIO_LIHypochloremia, a condition of predicted WNK1 activation, in PAH patients results in more severe RV dysfunction. C_LI

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Prisco, S. Z., Eklund, M., Thenappan, T., Prins, K. W.. 2021-06-22. With No Lysine Kinase 1 Promotes Right Ventricular Dysfunction Via Glucotoxicity. https://doi.org/10.1101/2021.06.22.449476

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