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.
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.