Ischemic preconditioning increases iNOS transcript levels in conscious rabbits via a nitric oxide-dependent mechanism
Ischemic preconditioning increases iNOS transcript levels in conscious rabbits via a nitric oxide-dependent mechanism
复制标题
DOI：
10.1006/jmcc.1999.0983
复制
发表时间：
1999-08-01
影响因子：
5
通讯作者：
Bolli, R
中科院分区：
文献类型：
--
作者：
Jones, WK;Flaherty, MP;Bolli, R
最近的研究表明iNOS是缺血预处理（PC）后期的中介。然而，iNOS活性的诱导是否由转录、转录后、翻译或翻译后机制介导尚不清楚。为了解决这个问题，我们分离并测序了预处理兔心肌中表达的部分iNOS cDNA。使用由该序列生成的兔特异性探针，我们测量了缺血PC[6个周期4分钟闭塞/4分钟再灌注（O/R）]后iNOS转录物的稳态水平。缺血PC后3小时，缺血/再灌注区iNOS mRNA水平相对于非缺血区和对照家兔增加约3倍。这种mRNA水平的增加被NOS抑制剂n - ω -硝基- l -精氨酸预处理完全消除。相反。一氧化氮供体硝酸甘油诱导的iNOS mRNA水平升高与缺血PC诱导的相似。我们得出结论，在清醒的家兔中，缺血PC诱导iNOS mRNA水平升高，而这种诱导是由PC刺激期间一氧化氮生成增加引起的。这些结果提供了直接证据，表明iNOS的上调是心脏对短暂缺血应激的自然反应，而一氧化氮本身，在没有缺血的情况下，上调心肌iNOS转录物水平，这一发现可能对硝酸盐治疗有启示。这种以前未被认识到的NO依赖的iNOS mRNA上调可能在晚期PC的发展以及许多其他与NO有关的病理生理条件中发挥重要作用。(C) 1999学术出版社。
Recent studies implicate iNOS as the mediator of the late phase of ischemic preconditioning (PC). However, it is unknown whether induction of iNOS activity is mediated by transcriptional, post-transcriptional, translational, or post-translational mechanisms. To address this issue, we isolated and sequenced a partial iNOS cDNA expressed in preconditioned rabbit myocardium. Using a rabbit-specific probe generated from this sequence, we measured the steady state levels of the iNOS transcript after ischemic PC [six cycles of 4-min occlusion/4-min reperfusion (O/R)]. Three hours after ischemic PC, the iNOS mRNA levels in the ischemic/reperfused region were increased approximately three-fold relative to samples from the non-ischemic region and from control rabbits. This increase in mRNA levels was completely abolished by pretreatment with the NOS inhibitor N-omega-nitro-L-arginine. Conversely. administration of the NO donor nitroglycerin induced an increase in iNOS mRNA levels similar to that induced by ischemic PC. We conclude that in the conscious rabbit, ischemic PC induces an increase in iNOS mRNA levels, and that this induction is triggered by increased generation of NO during the PC stimulus, These results provide direct evidence that upregulation of iNOS is a natural response of the heart to a brief ischemic stress and that NO itself, in the absence of ischemia, upregulates myocardial iNOS transcript levels, a finding that may have implications for nitrate therapy. This previously unrecognized NO-dependent upregulation of iNOS mRNA is likely to play an important role in the development of late PC as well as in many other pathophysiological conditions in which NO is implicated. (C) 1999 Academic Press.