With No Lysine Kinase 1 Promotes Metabolic Derangements and RV Dysfunction in Pulmonary Arterial Hypertension.
AMPK, adenosine monophosphate-activated protein kinase
AS160, 160 kDa substrate of the Akt serine/threonine kinase
DCA, dicarboxylic fatty acid
FAO, fatty acid oxidation
GLO1, glyoxalase 1
GLO2, glyoxalase 2
GLUT1, glucose transporter 1
GLUT4, glucose transporter 4
LV, left ventricle/ventricular
MCT, monocrotaline
MCT-V, monocrotaline-vehicle
PAH, pulmonary arterial hypertension
PTM, post-translationally modify/modifications
PV, pressure-volume
PVR, pulmonary vascular resistance
RA, right atrial
RV, right ventricle/ventricular
RVD, right ventricular dysfunction
TCA, tricarboxylic acid
Tau/τ, right ventricular relaxation time
UDP-GlcNAC, uridine diphosphate N-acetylglucosamine
WNK, with no lysine kinase
lipotoxicity
metabolism
mitochondria
pulmonary arterial hypertension
right ventricular dysfunction
with no lysine kinase 1
Journal
JACC. Basic to translational science
ISSN: 2452-302X
Titre abrégé: JACC Basic Transl Sci
Pays: United States
ID NLM: 101677259
Informations de publication
Date de publication:
Nov 2021
Nov 2021
Historique:
received:
23
06
2021
revised:
31
08
2021
accepted:
08
09
2021
entrez:
6
12
2021
pubmed:
7
12
2021
medline:
7
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34869947
doi: 10.1016/j.jacbts.2021.09.004
pii: S2452-302X(21)00276-X
pmc: PMC8617575
doi:
Types de publication
Journal Article
Langues
eng
Pagination
834-850Subventions
Organisme : NHLBI NIH HHS
ID : F32 HL154533
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL140100
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL144472
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002494
Pays : United States
Informations de copyright
© 2021 The Authors.
Déclaration de conflit d'intérêts
Dr Prisco was supported by the National Institutes of Health (NIH) (F32 HL154533 and T32 HL144472), a University of Minnesota Clinical and Translational Science award (NIH UL1 TR002494), and a University of Minnesota Medical School Academic Investment Educational Program Grant. Dr Thenappan was supported by the Cardiovascular Medical Research and Education Fund and the University of Minnesota Futures Grant. Dr Prins was supported by National Institutes of Health (K08 HL140100), the Cardiovascular Medical Research and Education Fund, a Lillehei Heart Institute Cardiovascular Seed Grant, the University of Minnesota Faculty Research Development Grant, the United Therapeutics Jenesis Award, and an American Lung Association Innovative Award (IA-816386). Dr Thenappan has served on advisory boards for Actelion, United Therapeutics, Altavant Sciences, and Aria CV; and has received research funding for clinical trials from United Therapeutics, Aria CV, Gossimer Bio, and Acceleron. Dr Prins has served on advisory boards for Actelion and Edwards; and has received grant funding from United Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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