Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice

• Published in: Circulation (New York, N.Y.) N.Y.), 2001-07, Vol.104 (4), p.448-454
• Main Authors: KUHLENCORDT, Peter J, GYURKO, Robert, HAN, Fred, SCHERRER-CROSBIE, Marielle, ARETZ, Thomas H, HAJJAR, Roger, PICARD, Michael H, HUANG, Paul L
• Format: Article
• Language: English
• Subjects: Animals; Aorta, Abdominal - metabolism; Aorta, Abdominal - pathology; Aorta, Thoracic - metabolism; Aorta, Thoracic - pathology; Aortic Aneurysm - genetics; Aortic Aneurysm - pathology; Aortic Aneurysm - physiopathology; Apolipoproteins - genetics; Arteriosclerosis - genetics; Arteriosclerosis - pathology; Arteriosclerosis - physiopathology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - genetics; Blood Pressure - physiology; Cardiology. Vascular system; Cardiovascular Diseases - genetics; Cardiovascular Diseases - pathology; Cardiovascular Diseases - physiopathology; Female; Genotype; Heart Rate - genetics; Heart Rate - physiology; Lipid Metabolism; Lipids - blood; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Ischemia - genetics; Myocardial Ischemia - pathology; Myocardial Ischemia - physiopathology; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/hc2901.091399

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. 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. 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.