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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.

journal of the american heart association

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