Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling
Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling
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DOI：
10.1073/pnas.0404136101
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发表时间：
2004-11-09
影响因子：
11.1
通讯作者：
Hare, JM
中科院分区：
文献类型：
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作者：
Khan, SA;Lee, K;Hare, JM
尽管超氧化物 (O-2(.-)) 和一氧化氮之间的相互作用是许多生理和病理生理过程的基础，但人们对这种串扰在酶水平上的调节知之甚少。在此，我们证明黄嘌呤氧化还原酶（XOR）（一种原型超氧化物 O-2(.-) 生成酶）和神经元一氧化氮合酶 (NOS1) 共免疫沉淀并共定位于心肌细胞的肌浆网中。 NOS1（但不是内皮NOS、NOS3）的缺乏会导致XOR介导的O-2(.-)产生显着增加，这反过来又以别嘌呤醇的XOR抑制可逆的方式抑制心肌兴奋-收缩耦合。这些数据证明一氧化氮和 O-2(.-) 生成酶之间存在独特的相互作用，从而解释了这些信号通路之间的串扰；这些发现证明了 NOS1 的直接抗氧化机制，并对越来越多的 XOR 活性增加发挥作用的疾病状态具有病理生理学意义。
Although interactions between superoxide (O-2(.-)) and nitric oxide underlie many physiologic and pathophysiologic processes, regulation of this crosstalk at the enzymatic level is poorly understood. Here, we demonstrate that xanthine oxidoreductase (XOR), a prototypic superoxide O-2(.-)-producing enzyme, and neuronal nitric oxide synthase (NOS1) coimmunoprecipitate and colocalize in the sarcoplasmic reticulum of cardiac myocytes. Deficiency of NOS1 (but not endothelial NOS, NOS3) leads to profound increases in XOR-mediated O-2(.-) production, which in turn depresses myocardial excitation-contraction coupling in a manner reversible by XOR inhibition with allopurinol. These data demonstrate a unique interaction between a nitric oxide and an O-2(.-)-generating enzyme that accounts for crosstalk between these signaling pathways; these findings demonstrate a direct antioxidant mechanism for NOS1 and have pathophysiologic implications for the growing number of disease states in which increased XOR activity plays a role.