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

• Published in: Journal of the American Heart Association 2018-03, Vol.7 (5), p.n/a
• Main Authors: Fancher, Ibra S., Ahn, Sang Joon, Adamos, Crystal, Osborn, Catherine, Oh, Myung‐Jin, Fang, Yun, Reardon, Catherine A., Getz, Godfrey S., Phillips, Shane A., Levitan, Irena
• Format: Article
• Language: English
• Subjects: Animals; Aorta - metabolism; Aorta - pathology; Aortic Diseases - genetics; Aortic Diseases - metabolism; Aortic Diseases - pathology; Aortic Diseases - physiopathology; atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Atherosclerosis - physiopathology; Cells, Cultured; Cholesterol - blood; Disease Models, Animal; Endothelial Cells - metabolism; Endothelial Cells - pathology; endothelial dysfunction; endothelial shear stress; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiopathology; hypercholesterolemia; Hypercholesterolemia - genetics; Hypercholesterolemia - metabolism; Hypercholesterolemia - pathology; Hypercholesterolemia - physiopathology; K channel; Kir channels; Male; Mesenteric Arteries - metabolism; Mesenteric Arteries - physiopathology; Mice, Inbred C57BL; Mice, Knockout, ApoE; nitric oxide; Nitric Oxide - metabolism; Original Research; Plaque, Atherosclerotic; Potassium Channels, Inwardly Rectifying - deficiency; Potassium Channels, Inwardly Rectifying - genetics; Potassium Channels, Inwardly Rectifying - metabolism; Signal Transduction; vascular endothelium; Vasodilation
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.117.007430

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.