Na+/H+ exchanger-1 inhibitors decrease myocardial superoxide production via direct mitochondrial action
Na+/H+ exchanger-1 inhibitors decrease myocardial superoxide production via direct mitochondrial action
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DOI：
10.1152/japplphysiol.90616.2008
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发表时间：
2008-12-01
影响因子：
3.3
通讯作者：
Ennis, Irene L.
中科院分区：
文献类型：
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作者：
Garciarena, Carolina D.;Caldiz, Claudia I.;Ennis, Irene L.
Garciarena CD，Caldiz CI，Correa MV，Schinella GR，莫斯卡SM，Chiappe de Cingolani GE，Cingolani HE，Ennis IL. Na+/H+交换器-1抑制剂通过直接线粒体作用减少心肌超氧化物的产生。J Appl Physiol 105：1706-1713，2008.首次发表于2008年9月18日; doi：10.1152/japplphysiol.90616.2008。- 在猫心肌中评估Na+/H+交换器-1（NHE-1）抑制剂降低活性氧（ROS）产生的直接线粒体作用的可能性。血管紧张素II和内皮素-1诱导NADPH氧化酶（NOX）依赖性增加阴离子超氧阴离子（O-2（-））的产生，通过化学发光检测。三种不同的NHE-1抑制剂[cariporide，BIIB-723和EMD-87580]没有ROS清除剂活性，阻止了这种增加。线粒体似乎是通过“ROS诱导的ROS释放机制”释放的NOx依赖性ROS的来源，该机制被线粒体ATP敏感性钾通道阻断剂5-羟基癸酸酯和格列本脲、鱼藤酮对电子传递链复合物I的抑制以及环孢菌素A对渗透性转换孔（MPTP）的抑制所减弱。Cariporide还阻止了由二氮嗪开放mK（ATP）诱导的O-2（-）产生。在分离的线粒体中评价Ca 2+诱导的肿胀作为MPTP形成的指标。Cariporide降低线粒体肿胀的程度与环孢菌素A和bongkrekic酸相同，证实了其直接的线粒体作用。正如预期的那样，O-2（-）产生的增加刺激ERK 1/2和p90核糖体S6激酶磷酸化。这也被cariporide阻止，为NHE-1抑制剂在阻止ROS释放中的直接线粒体作用的存在提供了额外的支持。总之，我们报告了NHE-1抑制剂的线粒体作用，这应该使我们重新审视或重新解释以前关于其在几种心脏疾病（如缺血再灌注损伤和心脏肥大和衰竭）中的有益作用的具有里程碑意义的观察。需要进一步的研究来阐明这些药物在钝化MPTP形成和ROS释放方面的确切机制和作用部位。
Garciarena CD, Caldiz CI, Correa MV, Schinella GR, Mosca SM, Chiappe de Cingolani GE, Cingolani HE, Ennis IL. Na+/H+ exchanger-1 inhibitors decrease myocardial superoxide production via direct mitochondrial action. J Appl Physiol 105: 1706-1713, 2008. First published September 18, 2008; doi:10.1152/japplphysiol.90616.2008. - 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. Ca2+-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.