title: Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice.
abstract: BACKGROUND
  To test whether deficiency in endothelial nitric oxide synthase (eNOS) affects atherosclerosis development, we compared lesion formation in apolipoprotein E (apoE)/eNOS-double knockout (DKO) and apoE-knockout (KO) control animals.
  
  
  RESULTS
  After 16 weeks of "Western-type" diet, apoE/eNOS-DKO males and females showed significant increases in lesion area of 93.6% and 59.2% compared with apoE-KO mice. All apoE/eNOS-DKO animals studied developed peripheral coronary arteriosclerosis, associated with perivascular and myocardial fibrosis, whereas none of the apoE-KO mice did. Transthoracic echocardiography showed a significantly increased left ventricular wall thickness and decreased fractional shortening in DKO animals. Mean arterial pressure was increased in DKO mice and was comparable in degree to eNOS-KO animals. Male DKO animals developed atherosclerotic abdominal aneurysms and aortic dissection.
  
  
  CONCLUSIONS
  eNOS deficiency increases atherosclerosis in Western-type diet-fed apoE-KO animals and introduces coronary disease and an array of cardiovascular complications, including spontaneous aortic aneurysm and dissection. This phenotype constitutes the first murine model to demonstrate distal coronary arteriosclerosis associated with evidence of myocardial ischemia, infarction, and heart failure. Hypertrophy and reduced left ventricular function cannot be explained by increased blood pressure alone, because eNOS-KO animals do not develop these complications.
authors.affiliation: Cardiovascular Research Center, Cardiology Division, Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Kuhlencordt
authors.forename: R
authors.initials: R
authors.lastname: Gyurko
authors.forename: F
authors.initials: F
authors.lastname: Han
authors.forename: M
authors.initials: M
authors.lastname: Scherrer-Crosbie
authors.forename: T H
authors.initials: TH
authors.lastname: Aretz
authors.forename: R
authors.initials: R
authors.lastname: Hajjar
authors.forename: M H
authors.initials: MH
authors.lastname: Picard
authors.forename: P L
authors.initials: PL
authors.lastname: Huang
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D001014:Aortic Aneurysm / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001053:Apolipoproteins / Q000235:genetics*; D001161:Arteriosclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D002318:Cardiovascular Diseases / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D005838:Genotype; D006339:Heart Rate / Q000235:genetics / Q000502:physiology; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III
chemical_list: D001053:Apolipoproteins; D008055:Lipids; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse