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Development of genetically engineered mice lacking all three nitric oxide synthases.
Masato Tsutsui1, Hiroaki Shimokawa, Tsuyoshi Morishita
1Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Japan. mt2498@med.uoeh-u.ac.jp
Journal of Pharmacological Sciences
|October 13, 2006
Summary
Mice lacking all three nitric oxide synthase (NOS) genes exhibit reduced survival and fertility, developing conditions like nephrogenic diabetes insipidus and spontaneous arteriosclerosis, highlighting NOS
Area of Science:
- Physiology
- Molecular Biology
- Cardiovascular Science
Background:
- Nitric oxide (NO) is a crucial signaling molecule produced by three isoforms of nitric oxide synthase (NOS): neuronal (nNOS), inducible (iNOS), and endothelial (eNOS).
- The complex interplay and compensatory mechanisms among NOS isoforms obscure the precise physiological and pathological roles of endogenous NO.
- Understanding the systemic function of NO requires a model that eliminates all NOS isoforms simultaneously.
Purpose of the Study:
- To investigate the systemic functions of endogenous nitric oxide (NO) by creating and analyzing mice lacking all three NOS isoforms (n/i/eNOS(-/-)).
- To elucidate the critical roles of the NOS system in maintaining physiological homeostasis, particularly cardiovascular health.
Main Methods:
- Generation of triple knockout mice (n/i/eNOS(-/-)) with complete disruption of all three NOS genes.
- Verification of absent NOS expression and activity in knockout mice, with and without lipopolysaccharide challenge.
- Phenotypic analysis of n/i/eNOS(-/-) mice, including assessment of survival, fertility, and development of specific physiological conditions.
Main Results:
- Triply n/i/eNOS(-/-) mice were viable but displayed significantly reduced survival and fertility rates compared to wild-type controls.
- Key phenotypes observed included polyuria, polydipsia, and renal unresponsiveness to vasopressin, indicative of nephrogenic diabetes insipidus.
- Spontaneous development of arteriosclerosis and a cluster of cardiovascular risk factors were evident in the n/i/eNOS(-/-) mice.
Conclusions:
- Systemic deletion of all three NOS isoforms leads to the spontaneous development of cardiovascular diseases in mice.
- These findings demonstrate a critical role for the endogenous NOS system in maintaining cardiovascular homeostasis.
- The study provides the first direct evidence for the essential contribution of NO produced by all three NOS isoforms to overall physiological balance.
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