Hypercholesterolemia-Induced Loss of Flow-Induced Vasodilation and Lesion Formation in Apolipoprotein E-Deficient Mice Critically Depend on Inwardly Rectifying K+ Channels

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 and results: 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.

Keywords: K channel; Kir channels; atherosclerosis; endothelial dysfunction; endothelial shear stress; hypercholesterolemia; nitric oxide; vascular endothelium.