The inhibition of the with no lysine kinase 1 (WNK1) protein through the administration of the small molecule WNK463 resulted in several beneficial effects in a rat model of pulmonary arterial hypertension (PAH).
These results, published in the Journal of the American College of Cardiology: Basic to Translational Science, showed that the administration of WNK463 helped improve right ventricular (RV) hypertrophy as well as systolic and diastolic functions in the PAH model. These changes, however, did not alter pulmonary vascular disease severity.
The study authors stated, “WNK463 treatment augmented RV function without significantly altering PAH severity. Thus, WNK1 signaling may be a pharmacological target to enhance RV function, a currently untreatable and lethal consequence of PAH.”
Treatment reduced the levels of glucose transporter (GLUT) 1 and GLUT4, which were upregulated in the PAH rat model. WNK463 also helped reduce and restore RV glucose metabolite levels, such as those from the hexosamine biosynthetic, glycolytic, and pentose phosphate pathways, to levels seen in control animals.
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Inhibition of WNK1 also reduced excess glycation and O-linked-N-acetylglucosaminylation (O-GlcNAcylation) of proteins.
In addition, WNK463 administration helped to normalize mitochondrial homeostasis by activating adenosine monophosphate-activated protein kinase (AMPK), increasing mitochondrial density, and preventing the downregulation of several mitochondrial metabolic proteins. Treatment also helped to mitigate secondary effects of altered mitochondrial fatty acid oxidation.
The article found that in a cohort of 217 PAH patients, those with hypochloremia, a condition resulting in increased WNK1 activation, had more severe RV dysfunction. PAH patients with hypochloremia had higher right atrial pressure and a more steep decline in cardiac output as pulmonary vascular resistance increased than those without hypochloremia.
In the preclinical portion of the paper, male Sprague Dawley rats were given subcutaneous injections of either monocrotaline (MCT; 60 mg/kg) to induce PAH symptoms or phosphate-buffered saline (control rats). After 2 weeks, the rats that received MCT were given daily intraperitoneal injections of either 3 mg/kg WNK463 or the injection vehicle only (MCT-V) for 10 days before the analysis was performed.
Prisco SZ, Eklund M, Raveendran R, Thenappan T, Prins KW. With no lysine kinase 1 promotes metabolic derangements and RV dysfunction in pulmonary arterial hypertension. JACC Basic Transl Sci. 2021;6(11):834-850. doi:10.1016/j.jacbts.2021.09.004