Significant Deterioration of Anti-atherogenic Efficacy of Nebivolol in a Double (apolipoprotein E and Endothelial Nitric Oxide Synthase) Knockout Mouse Model of Atherosclerosis in Comparison to Single (apolipoprotein E) Knockout Model

Since 1992 the mouse has become an excellent model for experimental atherosclerosis research. Until 1992, the diet induced atherosclerosis mouse model has been used effectively, but the lesions tended to be small and were limited to early fatty-streak stage. In 1992 the first line of gene targeted animal models, namely apolipoprotein E (apoE)-single knockout mice was developed. Of the genetically engineered models, the apoE-deficient model was the only one that developed extensive atherosclerotic lesions on a chow diet. The creation of apoE-single knockout mice has changed the face of atherosclerosis research (1). In 2001, more sophisticated model of atherogenesis: apoE and endothelial nitric oxide synthase (eNOS)-double knockout mice has been created independently in two laboratories (2, 3). It has shown that chronic deficiency of eNOS increases atherosclerosis in apoE-knockout mouse model. Furthermore, in the absence of eNOS, peripheral coronary disease, chronic myocardial ischemia, heart failure, and an array of vascular complications develop that have not been observed in apoEknockout animals. However, soon it has occurred that there was a big problem with the model: apoE and eNOS-double knockout mice bred extremely poor. In spite of this (since the model is excellent), we decided that after our experiments with nebivolol in apoE-single knockout mice (4, 5), we would try to use apoE and eNOS-double knockout mice to investigate the mechanism of nebivolol anti-atherogenic action.