Development of genetically engineered mice lacking all three nitric oxide synthases
Development of genetically engineered mice lacking all three nitric oxide synthases
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DOI：
10.1254/jphs.cpj06015x
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发表时间：
2006-10-01
影响因子：
3.5
通讯作者：
Yanagihara, Nobuyuki
中科院分区：
文献类型：
--
作者：
Tsutsui, Masato;Shimokawa, Hiroaki;Yanagihara, Nobuyuki
一氧化氮（NO）是一种广泛存在于各种组织器官中的物质，在生理和病理条件下发挥着多种生物学作用。NO由三种不同的NO合酶（NOS）亚型合成：神经元型、诱导型和内皮型NOS。由于NOS同工酶之间的相互代偿作用，内源性NO在我们体内的最终作用仍有待充分阐明。为了解决这一点，我们已经成功地开发了小鼠，其中所有三个NOS基因都被完全破坏。在脂多糖处理前后，三重n/i/eNOS（-/-）小鼠中NOS表达和活性完全缺失。虽然三重n/i/eNOS（-/-）小鼠是可行的，但与野生型小鼠相比，它们的存活率和生育率显著降低。我们首先注意到的这些小鼠的表型是多尿、多饮和肾对加压素无反应，这些特征与肾源性尿崩症一致。我们随后观察到，在这些小鼠中，动脉硬化是自发发展的，伴随着心血管危险因素的聚集。这些结果提供了第一个证据表明，所有三个NOS的系统性缺失导致小鼠的各种心血管疾病，证明了内源性NOS系统在维持心血管稳态中的关键作用。
Nitric oxide (NO) is produced in almost all tissues and organs, exerting multiple biological actions under both physiological and pathological conditions. NO is synthesized by three different isoforms of NO synthase (NOS): neuronal, inducible, and endothelial NOSs. Due to the substantial compensatory interactions among the NOS isoforms, the ultimate roles of endogenous NO in our body still remain to be fully elucidated. To address this point, 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 phenotypes of those mice that we first noticed 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 the systemic deletion of all three NOSs causes a variety of cardiovascular diseases in mice, demonstrating a critical role of the endogenous NOSs system in maintaining cardiovascular homeostasis.