Coronary endothelial dysfunction prevented by small-conductance calcium-activated potassium channel activator in mice and patients with diabetes.
Aged
Animals
Cells, Cultured
Coronary Artery Disease
/ diagnosis
Coronary Vessels
/ drug effects
Diabetes Mellitus, Experimental
Diabetes Mellitus, Type 2
/ complications
Endothelium, Vascular
/ drug effects
Female
Humans
Indoles
/ pharmacology
Male
Mice
Oximes
/ pharmacology
Signal Transduction
Small-Conductance Calcium-Activated Potassium Channels
/ drug effects
Vasodilation
/ drug effects
SK channels
cardioplegia
coronary microcirculation
diabetes
endothelial function
hypoxia
ischemia
Journal
The Journal of thoracic and cardiovascular surgery
ISSN: 1097-685X
Titre abrégé: J Thorac Cardiovasc Surg
Pays: United States
ID NLM: 0376343
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
10
04
2019
revised:
30
12
2019
accepted:
31
01
2020
pubmed:
23
3
2020
medline:
3
2
2021
entrez:
23
3
2020
Statut:
ppublish
Résumé
To investigate coronary endothelial protection of a small-conductance calcium-activated potassium (SK) channel activator against a period of cardioplegic-hypoxia and reoxygenation (CP-H/R) injury in mice and patients with diabetes (DM) and those without diabetes (nondiabetic [ND]). Mouse small coronary arteries/heart endothelial cells (MHECs) and human coronary arterial endothelial cells (HCAECs) were dissected from the harvested hearts of mice (n = 16/group) and from discarded right atrial tissue samples of patients with DM and without DM (n = 8/group). The SK current density of MHECs was measured. The in vitro small arteries/arterioles, MHECs, and HCAECs were subjected to 60 minutes of CP hypoxia, followed by 60 minutes of oxygenation. Vessels were treated with or without the selective SK activator NS309 for 5 minutes before and during CP hypoxia. DM and/or CP-H/R significantly inhibited the total SK currents of MHECs and HCAECs and significantly diminished the mouse coronary relaxation response to NS309. Administration of NS309 immediately before and during CP hypoxia significantly improved the recovery of coronary endothelial function, as demonstrated by increased relaxation responses to adenosine 5'-diphosphate and substance P compared with those seen in controls (P < .05). This protective effect was more pronounced in vessels from ND mice and patients compared with DM mice and patients (P < .05). Cell surface membrane SK3 expression was significantly reduced after hypoxia, whereas cytosolic SK3 expression was greater than that of the sham control group (P < .05). Application of NS309 immediately before and during CP hypoxia protects mouse and human coronary microvasculature against CP-H/R injury, but this effect is diminished in the diabetic coronary microvasculature. SK inhibition/inactivation and/or internalization/redistribution may contribute to CP-H/R-induced coronary endothelial and vascular relaxation dysfunction.
Identifiants
pubmed: 32199659
pii: S0022-5223(20)30426-8
doi: 10.1016/j.jtcvs.2020.01.078
pmc: PMC7439127
mid: NIHMS1564237
pii:
doi:
Substances chimiques
6,7-dichloro-1H-indole-2,3-dione 3-oxime
0
Indoles
0
Oximes
0
Small-Conductance Calcium-Activated Potassium Channels
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e263-e280Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL046716
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103652
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128831
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL136347
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL127072
Pays : United States
Informations de copyright
Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
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