2007 Fiscal Year Final Research Report Summary
Elucidation of the pathogenesis of life style-related diseases and development of their therapeutic strategy
| Project/Area Number |
18591010
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Metabolomics
|
|---|
| Research Institution | University of Occupational and Environmental Health, Japan |
|---|
Principal Investigator |
NAKASHIMA Yasuhide University of Occupational and Environmental Health, Japan, Emeritus Professor (20038780)
|
|---|
| Project Period (FY) |
2006 – 2007
|
| Keywords | nitric oxide synthase / genetically engineered mice / arteriosclerosis / myocardial infarction / metabolic syndrome |
|---|
| Research Abstract |
The nitric oxide synthase (NOS) system consists of three isoforms: neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS). The roles of the NOS system in vivo have been widely studied using non-selective NOS inhibitors. However, since the NOS inhibitors possess multiple non-specific actions, the authentic roles of the NOS system in our body remain to be fully elucidated. To address this issue, we have recently developed the NOS system-deficient mice (triply n/i/eNOS^<-1-> mice) (PNAS 2005).
Although the triply NOS^<-/-> mouse was not embryo-lethal fortunately, survival rate was markedly reduced as compared with wild-type mice. Intriguingly, more than half of the triply NOS^<-/-> mice died due to spontaneous myocardial infarction associated with severe coronary arteriosclerosis.
Notably, although it is well established that eNOS exerts antiarteriosclerotic effects, and although eNOS^<-/-> mice manifest accumulation of cardiovascular risk factors, eNOS*<-/-> mice do not spontaneousl
… More
y develop arteriosclerotic vascular lesion formation. This inconsistency is explained by a compensatory mechanism by other NOSs that are not genetically disrupted. Thus, our triply NOS^<-/-> mouse is a powerful experimental tool to solve this problem and to investigate the roles of the NOS system.
The triply NOS^<-/-> mice manifested metabolic syndrome, including visceral obesity, hypertension, hypertriglyceridemia, and impaired glucose tolerance. In addition, the triply NOS^<-/-> mice exhibited left ventricular hypertrophy and diastolic dysfunction. Importantly, an increase in plasma angiotensin II level and upregulation of cardiac angiotensin-converting enzyme were noted in the triply NOS^<-/-> mice, suggesting an involvement of activation of the renin-angiotensin system in the pathogenesis of cardiovascular disorders in the triply NOS^<-/-> mice.
These results provide the first direct evidence that genetic disruption of the whole NOS system causes spontaneous myocardial infarction associated with multiple cardiovascular risk factors of metabolic origin in mice in vivo, demonstrating the critical role of the endogenous NOS system in maintaining cardiovascular homeostasis. Less
|
