Hypercholesterolemia-Induced Loss of Flow-Induced Vasodilation and Lesion Formation in Apolipoprotein E-Deficient Mice Critically Depend on Inwardly Rectifying K+ Channels.
J Am Heart Assoc
; 7(5)2018 03 03.
Article
en En
| MEDLINE
| ID: mdl-29502106
ABSTRACT
BACKGROUND:
Hypercholesterolemia-induced decreased availability of nitric oxide (NO) is a major factor in cardiovascular disease. We previously established that cholesterol suppresses endothelial inwardly rectifying K+ (Kir) channels and that Kir2.1 is an upstream mediator of flow-induced NO production. Therefore, we tested the hypothesis that suppression of Kir2.1 is responsible for hypercholesterolemia-induced inhibition of flow-induced NO production and flow-induced vasodilation (FIV). We also tested the role of Kir2.1 in the development of atherosclerotic lesions. METHODS ANDRESULTS:
Kir2.1 currents are significantly suppressed in microvascular endothelial cells exposed to acetylated-low-density lipoprotein or isolated from apolipoprotein E-deficient (Apoe-/- ) mice and rescued by cholesterol depletion. Genetic deficiency of Kir2.1 on the background of hypercholesterolemic Apoe-/- mice, Kir2.1+/-/Apoe-/- exhibit the same blunted FIV and flow-induced NO response as Apoe-/- or Kir2.1+/- alone, but while FIV in Apoe-/- mice can be rescued by cholesterol depletion, in Kir2.1+/-/Apoe-/- mice cholesterol depletion has no effect on FIV. Endothelial-specific overexpression of Kir2.1 in arteries from Apoe-/- and Kir2.1+/-/Apoe-/- mice results in full rescue of FIV and NO production in Apoe-/- mice with and without the addition of a high-fat diet. Conversely, endothelial-specific expression of dominant-negative Kir2.1 results in the opposite effect. Kir2.1+/-/Apoe-/- mice also show increased lesion formation, particularly in the atheroresistant area of descending aorta.CONCLUSIONS:
We conclude that hypercholesterolemia-induced reduction in FIV is largely attributable to cholesterol suppression of Kir2.1 function via the loss of flow-induced NO production, whereas the stages downstream of flow-induced Kir2.1 activation appear to be mostly intact. Kir2.1 channels also have an atheroprotective role.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Aorta
/
Enfermedades de la Aorta
/
Vasodilatación
/
Endotelio Vascular
/
Canales de Potasio de Rectificación Interna
/
Aterosclerosis
/
Placa Aterosclerótica
/
Hipercolesterolemia
/
Arterias Mesentéricas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Am Heart Assoc
Año:
2018
Tipo del documento:
Article