KD025 Shifts Pulmonary Endothelial Cell Bioenergetics and Decreases Baseline Lung Permeability.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
/ analogs & derivatives
Adenosine Triphosphate
/ metabolism
Animals
Annexin A5
/ metabolism
Capillary Permeability
/ drug effects
Cell Movement
/ drug effects
Deoxyglucose
/ metabolism
Endothelial Cells
/ drug effects
Endothelium, Vascular
/ drug effects
Energy Metabolism
/ drug effects
Glycolysis
/ drug effects
Heterocyclic Compounds, 4 or More Rings
/ pharmacology
Hydrogen-Ion Concentration
L-Lactate Dehydrogenase
/ metabolism
Lung
/ drug effects
Male
Oxidative Phosphorylation
/ drug effects
Propidium
/ pharmacology
Rats
Rats, Inbred F344
Rats, Sprague-Dawley
Signal Transduction
/ drug effects
rho-Associated Kinases
/ metabolism
anion exchanger 2
bleomycin
caspase-3
hypoxia
rho kinase
Journal
American journal of respiratory cell and molecular biology
ISSN: 1535-4989
Titre abrégé: Am J Respir Cell Mol Biol
Pays: United States
ID NLM: 8917225
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
pubmed:
7
7
2020
medline:
24
11
2020
entrez:
7
7
2020
Statut:
ppublish
Résumé
KD025 is a ROCK2 inhibitor currently being tested in clinical trials for the treatment of fibrotic lung diseases. The therapeutic effects of KD025 are partly due to its inhibition of profibrotic pathways and fat metabolism. However, whether KD025 affects pulmonary microvascular endothelial cell (PMVEC) function is unknown, despite evidence that alveolar-capillary membrane disruption constitutes major causes of death in fibrotic lung diseases. We hypothesized that KD025 regulates PMVEC metabolism, pH, migration, and survival, a series of interrelated functional characteristics that determine pulmonary barrier integrity. We used PMVECs isolated from Sprague Dawley rats. KD025 dose-dependently decreased lactate production and glucose consumption. The inhibitory effect of KD025 was more potent compared with other metabolic modifiers, including 2-deoxy-glucose, extracellular acidosis, dichloroacetate, and remogliflozin. Interestingly, KD025 increased oxidative phosphorylation, whereas 2-deoxy-glucose did not. KD025 also decreased intracellular pH and induced a compensatory increase in anion exchanger 2. KD025 inhibited PMVEC migration, but fasudil (nonspecific ROCK inhibitor) did not. We tested endothelial permeability
Identifiants
pubmed: 32628869
doi: 10.1165/rcmb.2019-0435OC
pmc: PMC7528923
doi:
Substances chimiques
Annexin A5
0
Heterocyclic Compounds, 4 or More Rings
0
KD025
0
Propidium
36015-30-2
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
84477-87-2
Adenosine Triphosphate
8L70Q75FXE
Deoxyglucose
9G2MP84A8W
L-Lactate Dehydrogenase
EC 1.1.1.27
rho-Associated Kinases
EC 2.7.11.1
fasudil
Q0CH43PGXS
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
519-530Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL148069
Pays : United States
Organisme : American Heart Association-American Stroke Association
ID : 18CDA34080151
Pays : United States
Organisme : NHLBI NIH HHS
ID : R37 HL060024
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL060024
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL066299
Pays : United States
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