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

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 ( ) mice and rescued by cholesterol depletion. Genetic deficiency of Kir2.1 on the background of hypercholesterolemic mice, exhibit the same blunted FIV and flow-induced NO response as or alone, but while FIV in mice can be rescued by cholesterol depletion, in mice cholesterol depletion has no effect on FIV. Endothelial-specific overexpression of Kir2.1 in arteries from and mice results in full rescue of FIV and NO production in 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. 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.