TY - JOUR
T1 - Development of genetically engineered mice lacking all three nitric oxide synthase isoform
AU - Tsutsui, Masato
AU - Shimokawa, Hiroaki
AU - Morishita, Tsuyoshi
AU - Nakata, Sei
AU - Sabanai, Ken
AU - Nakashima, Yasuhide
AU - Yanagihara, Nobuyuki
PY - 2007/9
Y1 - 2007/9
N2 - The nitric oxide (NO) synthases (NOSs) system consists of three different isoforms, including neuronal (nNOS), inducible (iNOS), and endothelial NOSs (eNOS). The roles of NO in vivo have been extensively investigated in pharmacological studies with NOS inhibitors and in studies with mice lacking each NOS isoform. However, in the pharmacological studies, the specificity of NOS inhibitors continues to be an issue of debate, while in the studies with mice lacking each NOS isoform, compensatory mechanism by other NOSs appears to be involved. Thus, the ultimate roles of endogenous NO in our body still remain to be fully elucidated. To address this important issue, we have successfully developed mice in which all three NOS genes are completely disrupted. NOS expression and activities were totally absent in the triply n/i/eNOS -/- mice before and after treatment with lipopolysaccharide. While the triply n/i/eNOS-/- mice were viable, their survival and fertility rates were markedly reduced as compared with wild-type mice. The first noticeable phenotypes were polyuria, polydipsia, and renal unresponsiveness to vasopressin, characteristics consistent with nephrogenic diabetes insipidus. We subsequently observed that in those mice, arteriosclerosis is spontaneously developed with a clustering of cardiovascular risk factors. These results provide the first evidence that genetic disruption of all three NOSs causes a variety of cardiovascular diseases in mice in vivo, demonstrating the critical role of the endogenous NOSs system in maintaining cardiovascular homeostasis.
AB - The nitric oxide (NO) synthases (NOSs) system consists of three different isoforms, including neuronal (nNOS), inducible (iNOS), and endothelial NOSs (eNOS). The roles of NO in vivo have been extensively investigated in pharmacological studies with NOS inhibitors and in studies with mice lacking each NOS isoform. However, in the pharmacological studies, the specificity of NOS inhibitors continues to be an issue of debate, while in the studies with mice lacking each NOS isoform, compensatory mechanism by other NOSs appears to be involved. Thus, the ultimate roles of endogenous NO in our body still remain to be fully elucidated. To address this important issue, we have successfully developed mice in which all three NOS genes are completely disrupted. NOS expression and activities were totally absent in the triply n/i/eNOS -/- mice before and after treatment with lipopolysaccharide. While the triply n/i/eNOS-/- mice were viable, their survival and fertility rates were markedly reduced as compared with wild-type mice. The first noticeable phenotypes were polyuria, polydipsia, and renal unresponsiveness to vasopressin, characteristics consistent with nephrogenic diabetes insipidus. We subsequently observed that in those mice, arteriosclerosis is spontaneously developed with a clustering of cardiovascular risk factors. These results provide the first evidence that genetic disruption of all three NOSs causes a variety of cardiovascular diseases in mice in vivo, demonstrating the critical role of the endogenous NOSs system in maintaining cardiovascular homeostasis.
KW - Cardiovascular disease
KW - Knockout mouse
KW - Metabolic syndrom
KW - Nephrogenic diabetes insipidus
KW - Nitric oxide synthase
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U2 - 10.1248/yakushi.127.1347
DO - 10.1248/yakushi.127.1347
M3 - Review article
C2 - 17827917
AN - SCOPUS:34548440272
VL - 127
SP - 1347
EP - 1355
JO - Yakugaku Zasshi
JF - Yakugaku Zasshi
SN - 0031-6903
IS - 9
ER -