{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:46:01Z","timestamp":1792676761887,"version":"4.5.0"},"reference-count":64,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2018,3,6]]},"abstract":"Background<\/jats:title>Hypercholesterolemia\u2010induced decreased availability of nitric oxide (NO<\/jats:styled-content>) is a major factor in cardiovascular disease. We previously established that cholesterol suppresses endothelial inwardly rectifying K+<\/jats:sup>(Kir) channels and that Kir2.1 is an upstream mediator of flow\u2010inducedNO<\/jats:styled-content>production. Therefore, we tested the hypothesis that suppression of Kir2.1 is responsible for hypercholesterolemia\u2010induced inhibition of flow\u2010inducedNO<\/jats:styled-content>production and flow\u2010induced vasodilation (FIV<\/jats:styled-content>). We also tested the role of Kir2.1 in the development of atherosclerotic lesions.<\/jats:p><\/jats:sec>Methods and Results<\/jats:title>Kir2.1 currents are significantly suppressed in microvascular endothelial cells exposed to acetylated\u2013low\u2010density lipoprotein or isolated from apolipoprotein E\u2013deficient (Apoe<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) mice and rescued by cholesterol depletion. Genetic deficiency of Kir2.1 on the background of hypercholesterolemicApoe<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>mice,Kir2.1<\/jats:italic>+\/\u2212<\/jats:italic><\/jats:sup>\/Apoe<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>exhibit the same bluntedFIV<\/jats:styled-content>and flow\u2010inducedNO<\/jats:styled-content>response asApoe<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>orKir2.1<\/jats:italic>+\/\u2212<\/jats:italic><\/jats:sup>alone, but while FIV inApoe<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>mice can be rescued by cholesterol depletion, inKir2.1<\/jats:italic>+\/\u2212<\/jats:italic><\/jats:sup>\/Apoe<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>mice cholesterol depletion has no effect onFIV<\/jats:styled-content>. Endothelial\u2010specific overexpression of Kir2.1 in arteries fromApoe<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>andKir2.1<\/jats:italic>+\/\u2212<\/jats:italic><\/jats:sup>\/Apoe<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>mice results in full rescue ofFIV<\/jats:styled-content>andNO<\/jats:styled-content>production inApoe<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>mice with and without the addition of a high\u2010fat diet. Conversely, endothelial\u2010specific expression of dominant\u2010negative Kir2.1 results in the opposite effect.Kir2.1<\/jats:italic>+\/\u2212<\/jats:italic><\/jats:sup>\/Apoe<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>mice also show increased lesion formation, particularly in the atheroresistant area of descending aorta.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>We conclude that hypercholesterolemia\u2010induced reduction inFIV<\/jats:styled-content>is largely attributable to cholesterol suppression of Kir2.1 function via the loss of flow\u2010inducedNO<\/jats:styled-content>production, whereas the stages downstream of flow\u2010induced Kir2.1 activation appear to be mostly intact. Kir2.1 channels also have an atheroprotective role.<\/jats:p><\/jats:sec>","DOI":"10.1161\/jaha.117.007430","type":"journal-article","created":{"date-parts":[[2018,3,4]],"date-time":"2018-03-04T01:10:21Z","timestamp":1520125821000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":52,"title":["Hypercholesterolemia\u2010Induced Loss of Flow\u2010Induced Vasodilation and Lesion Formation in Apolipoprotein E\u2013Deficient Mice Critically Depend on Inwardly Rectifying K+<\/sup>Channels"],"prefix":"10.1161","volume":"7","author":[{"given":"Ibra S.","family":"Fancher","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, IL"},{"name":"Department of Physical Therapy, University of Illinois at Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Joon","family":"Ahn","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Adamos","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, IL"},{"name":"Department of Physical Therapy, University of Illinois at Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Osborn","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myung\u2010Jin","family":"Oh","sequence":"additional","affiliation":[{"name":"Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Fang","sequence":"additional","affiliation":[{"name":"Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine A.","family":"Reardon","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Godfrey S.","family":"Getz","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane A.","family":"Phillips","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy, University of Illinois at Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Levitan","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","first-page":"246","article-title":"Mechanoreception by the endothelium: mediators and mechanisms of pressure\u2010 and flow\u2010induced vascular responses","volume":"27","author":"Rubanyi GM","year":"1990","unstructured":"Rubanyi GM, Freay AD, Kauser K, Johns A, Harder DR. 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