Requirement of argininosuccinate lyase for systemic nitric oxide production.
Requirement of argininosuccinate lyase for systemic nitric oxide production.
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一氧化氮（NO）在多种生理和病理过程中发挥着关键作用。我们发现，精氨酸琥珀酸裂解酶 (Asl) 缺陷的亚效型小鼠模型表现出独特的表型，表现为多器官功能障碍和 NO 缺乏。在人类和小鼠中，Asl 的缺失会导致 NO 合成减少，这是由于内源性精氨酸合成减少以及细胞外精氨酸用于 NO 产生的利用减少。因此，通过进化在其他物种中看到的 ASL 除了催化活性之外还具有结构功能。重要的是，亚硝酸盐治疗挽救了亚效型 Asl 小鼠的组织自主性 NO 缺陷，而 NOS 独立的 NO 供体则恢复了 ASL 缺陷受试者的 NO 依赖性血管反应性。我们的数据表明 ASL 在 NOS 功能和 NO 稳态中的作用此前未被认识到。因此，ASL 可以作为在实验模型中操纵 NO 产生以及治疗 NO 相关疾病的靶标。
Nitric Oxide (NO) plays a critical role in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (Asl) deficiency exhibits a distinct phenotype manifest by multi-organ dysfunction and NO deficiency. Loss of Asl leads to reduced NO synthesis due to decreased endogenous arginine synthesis as well as reduced utilization of extracellular arginine for NO production in both humans and mice. Hence, ASL as seen in other species through evolution has a structural function in addition to its catalytic activity. Importantly, therapy with nitrite rescued the tissue autonomous NO deficiency in hypomorphic Asl mice, while a NOS independent NO donor restored NO-dependent vascular reactivity in subjects with ASL deficiency. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as treatment of NO-related diseases.