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钠氢交换体-1抑制剂通过直接的线粒体作用减少心肌超氧化物的产生。

Na+/H+ exchanger-1 inhibitors decrease myocardial superoxide production via direct mitochondrial action.

作者信息

Garciarena Carolina D, Caldiz Claudia I, Correa María V, Schinella Guillermo R, Mosca Susana M, Chiappe de Cingolani Gladys E, Cingolani Horacio E, Ennis Irene L

机构信息

Centro de Investigaciones Cardiovasces, Facultad de Ciencias Médicas, UNLP 60 y 120, 1900 La Plata, Argentina.

出版信息

J Appl Physiol (1985). 2008 Dec;105(6):1706-13. doi: 10.1152/japplphysiol.90616.2008. Epub 2008 Sep 18.

Abstract

The possibility of a direct mitochondrial action of Na(+)/H(+) exchanger-1 (NHE-1) inhibitors decreasing reactive oxygen species (ROS) production was assessed in cat myocardium. Angiotensin II and endothelin-1 induced an NADPH oxidase (NOX)-dependent increase in anion superoxide (O(2)(-)) production detected by chemiluminescence. Three different NHE-1 inhibitors [cariporide, BIIB-723, and EMD-87580] with no ROS scavenger activity prevented this increase. The mitochondria appeared to be the source of the NOX-dependent ROS released by the "ROS-induced ROS release mechanism" that was blunted by the mitochondrial ATP-sensitive potassium channel blockers 5-hydroxydecanoate and glibenclamide, inhibition of complex I of the electron transport chain with rotenone, and inhibition of the permeability transition pore (MPTP) by cyclosporin A. Cariporide also prevented O(2)(-) production induced by the opening of mK(ATP) with diazoxide. Ca(2+)-induced swelling was evaluated in isolated mitochondria as an indicator of MPTP formation. Cariporide decreased mitochondrial swelling to the same extent as cyclosporin A and bongkrekic acid, confirming its direct mitochondrial action. Increased O(2)(-) production, as expected, stimulated ERK1/2 and p90 ribosomal S6 kinase phosphorylation. This was also prevented by cariporide, giving additional support to the existence of a direct mitochondrial action of NHE-1 inhibitors in preventing ROS release. In conclusion, we report a mitochondrial action of NHE-1 inhibitors that should lead us to revisit or reinterpret previous landmark observations about their beneficial effect in several cardiac diseases, such as ischemia-reperfusion injury and cardiac hypertrophy and failure. Further studies are needed to clarify the precise mechanism and site of action of these drugs in blunting MPTP formation and ROS release.

摘要

在猫心肌中评估了钠/氢交换体-1(NHE-1)抑制剂直接作用于线粒体从而减少活性氧(ROS)生成的可能性。血管紧张素II和内皮素-1可诱导通过化学发光检测到的阴离子超氧阴离子(O₂⁻)生成增加,该过程依赖烟酰胺腺嘌呤二核苷酸磷酸氧化酶(NOX)。三种不具有ROS清除活性的不同NHE-1抑制剂[卡立泊来德、BIIB-723和EMD-87580]可阻止这种增加。线粒体似乎是由“ROS诱导的ROS释放机制”释放的依赖NOX的ROS的来源,线粒体ATP敏感性钾通道阻滞剂5-羟基癸酸和格列本脲、鱼藤酮对电子传递链复合体I的抑制以及环孢素A对通透性转换孔(MPTP)的抑制可减弱该机制。卡立泊来德还可阻止由二氮嗪开放线粒体ATP敏感性钾通道(mKATP)诱导的O₂⁻生成。在分离的线粒体中评估钙诱导的肿胀作为MPTP形成的指标。卡立泊来德可使线粒体肿胀程度降低至与环孢素A和膨润酸相同的水平,证实了其直接的线粒体作用。正如预期的那样,O₂⁻生成增加刺激了细胞外信号调节激酶1/2(ERK1/2)和p90核糖体S6激酶的磷酸化。这也被卡立泊来德阻止,为NHE-1抑制剂在阻止ROS释放方面存在直接的线粒体作用提供了额外支持。总之,我们报道了NHE-1抑制剂的线粒体作用,这应该促使我们重新审视或重新解释先前关于它们在几种心脏疾病(如缺血再灌注损伤、心脏肥大和心力衰竭)中有益作用的标志性观察结果。需要进一步研究以阐明这些药物在减弱MPTP形成和ROS释放方面的确切机制和作用位点。

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