application) The investigator's overall hypothesis is that physiologic production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) suppresses atherosclerosis, whereas pathologic production of NO by inducible NOS (iNOS) and neuronal NOS (nNOS) contributes to atherosclerosis. In order to test this hypothesis, it is necessary to separate the effects of the various NOS isoforms. Pharmacologic approaches are limited because NOS inhibitors, NO donors, and NO precursors do not distinguish between the isoforms. The investigator plans to use NOS knockout mice as specific tools to dissect out the roles of each NOS isoform in the molecular events of atherosclerosis. To study the cellular proliferative response, the investigator plans to quantify the response of NOS mutant mice to two well-defined models of vascular injury: cuff induced adventitial injury of the femoral artery, and filament induced endothelial injury of the carotid artery. To study the development of complex atherosclerotic lesions, the investigator will use apoE mutant mice as a model system. The investigator will generate double knockout mice that lack apoE and each NOS isoform to determine the effect of each isoform on apoE- deficiency atherosclerosis. To study the effects of NO on the molecular events that underlie atherogenesis, the investigator will determine which NOS isoform(s) is involved in peroxynitrite generation, and test whether peroxynitrite is essential for lipid peroxidation and endothelial cell activation.
Showing the most recent 10 out of 28 publications
