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 (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.

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