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With No Lysine Kinase 1 Promotes Metabolic Derangements and RV Dysfunction in Pulmonary Arterial Hypertension

ABSTRACT: Visual Abstract Highlights • Small molecule inhibition of WNK1 (WNK463) signaling mitigates upregulation of the membrane glucose channels GLUT1 and GLUT4, restores levels of several glucose metabolites, and decreases protein O-GlcNAcylation and glycation in the RV.• Quantitative proteomics of RV mitochondrial enrichments shows WNK463 treatment prevents down-regulation of several mitochondrial enzymes in the tricarboxylic acid cycle, fatty acid oxidation pathway, and the electron transport chain complexes.• Integration of proteomics and metabolomics analysis suggests WNK463 reduces glutaminolysis induction and lipotoxicity caused by impaired mitochondrial fatty acid oxidation.• WNK463 augments RV systolic and diastolic function independent of PAH severity.• Hypochloremia, a condition of predicted WNK1 activation in patients with PAH, is associated with more severe RV dysfunction. Summary 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.

SUBMITTER: Prisco S

PROVIDER: S-EPMC8617575 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Right ventricular (RV) dysfunction (RVD) is the most frequent cause of death in patients with pulmonary arterial hypertension. Although abnormal energy substrate use has been implicated in the development of chronic left heart failure, data describing such metabolic remodeling in RVD remain incomplete. Thus, we sought to characterize metabolic gene expression changes and mitochondrial dysfunction in functional and dysfunctional RV hypertrophy.Two different rat models of RV hypertrophy were studied. The model of RVD (SU5416/hypoxia) exhibited a significantly decreased gene expression of peroxisome proliferator-activated receptor-? coactivator-1?, peroxisome proliferator-activated receptor-? and estrogen-related receptor-?. The expression of multiple peroxisome proliferator-activated receptor-? coactivator-1? target genes required for fatty acid oxidation was similarly decreased. Decreased peroxisome proliferator-activated receptor-? coactivator-1? expression was also associated with a net loss of mitochondrial protein and oxidative capacity. Reduced mitochondrial number was associated with a downregulation of transcription factor A, mitochondrial, and other genes required for mitochondrial biogenesis. Electron microscopy demonstrated that, in RVD tissue, mitochondria had abnormal shape and size. Lastly, respirometric analysis demonstrated that mitochondria isolated from RVD tissue had a significantly reduced ADP-stimulated (state 3) rate for complex I. Conversely, functional RV hypertrophy in the pulmonary artery banding model showed normal expression of peroxisome proliferator-activated receptor-? coactivator-1?, whereas the expression of fatty acid oxidation genes was either preserved or unregulated. Moreover, pulmonary artery banding-RV tissue exhibited preserved transcription factor A mitochondrial expression and mitochondrial respiration despite elevated RV pressure-overload.Right ventricular dysfunction, but not functional RV hypertrophy in rats, demonstrates a gene expression profile compatible with a multilevel impairment of fatty acid metabolism and significant mitochondrial dysfunction, partially independent of chronic pressure-overload.

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With No Lysine Kinase 1 Promotes Metabolic Derangements and RV Dysfunction in Pulmonary Arterial Hypertension

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