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

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. Methods and Results-After 16 weeks of "Western-type" diet, apoE/eNOS-DKO ma les 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 myo cardial fibrosis, whereas none of the apoE-KO mice did. Transthoracic echoc ardiography showed a significantly increased left ventricular wall thicknes s and decreased fractional shortening in DKO animals. Mean arterial pressur e 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 cardiov ascular complications, including spontaneous aortic aneurysm and dissection . This phenotype constitutes the first murine model to demonstrate distal c oronary arteriosclerosis associated with evidence of myocardial ischemia, i nfarction, and heart failure. Hypertrophy and reduced left ventricular func tion cannot be explained by increased blood pressure alone, because eNOS-KO animals do not develop these complications.