Damage to mitochondrial complex I during cardiac ischemia reperfusion injury is reduced indirectly by anti-anginal drug ranolazine.
Damage to mitochondrial complex I during cardiac ischemia reperfusion injury is reduced indirectly by anti-anginal drug ranolazine.
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DOI：
10.1016/j.bbabio.2011.11.021
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发表时间：
2012-03
影响因子：
4.3
通讯作者：
Camara, Amadou K. S.
中科院分区：
文献类型：
--
作者：
Gadicherla, Ashish K.;Stowe, David F.;Antholine, William E.;Yang, Meiying;Camara, Amadou K. S.
雷诺嗪（Ranolazine, Ran）是一种抗心绞痛药物，是一种晚期Na+通道电流阻滞剂，也被认为可以减弱脂肪酸氧化和线粒体呼吸复合体I的活性，特别是在缺血时。在这项研究中，我们研究了Ran对心脏缺血/再灌注（IR）损伤的保护作用是否在线粒体水平上介导，特别是是否保护呼吸复合体I （NADH氧化还原酶）功能。我们在缺血30分钟前用Ran处理离体和灌注的豚鼠心脏，然后在缺血30分钟和/或缺血30分钟后再灌注10分钟时分离心脏线粒体。我们利用分光光度法和组织化学技术检测复合物I的活性，western blot分析复合物I亚基NDUFA9，电子顺磁共振检测复合物I Fe-S簇的活性，ELISA检测蛋白质乙酰化，天然凝胶组织化学染色检测呼吸超复合物组装，高压液相色谱检测心磷脂完整性；在IR期间测量心功能。与未处理的IR心脏相比，Ran处理的心脏显示出更高的复合物I活性和更高的可检测复合物I蛋白水平。Ran处理还通过Fe-S中心、超络合物组装和心磷脂完整性导致更规范化的电子转移。Ran复合物I结构和功能的改善与IR后心功能的改善有关。然而，Ran的这些保护作用不是通过对线粒体的直接作用介导的，而是通过胞质机制间接介导的，从而减少复合物I的氧化和更好的结构完整性。
Ranolazine (Ran), an anti-anginal drug, is a late Na+ channel current blocker that is also believed to attenuate fatty acid oxidation and mitochondrial respiratory complex I activity, especially during ischemia. In this study, we investigated if Ran's protective effect against cardiac ischemia/reperfusion (IR) injury is mediated at the mitochondrial level and specifically if respiratory complex I (NADH oxidoreductase) function is protected. We treated isolated and perfused guinea pig hearts with Ran just before 30 min ischemia and then isolated cardiac mitochondria at the end of 30 min ischemia and/or 30 min ischemia followed by 10 min reperfusion. We utilized spectrophotometric and histochemical techniques to assay complex I activity, western blot analysis for complex I subunit NDUFA9, electron paramagnetic resonance for activity of complex I Fe-S clusters, ELISA for determination of protein acetylation, native gel histochemical staining for respiratory supercomplex assemblies, and high pressure liquid chromatography for cardiolipin integrity; cardiac function was measured during IR. Ran treated hearts showed higher complex I activity and greater detectable complex I protein levels compared to untreated IR hearts. Ran treatment also led to more normalized electron transfer via Fe-S centers, supercomplex assembly and cardiolipin integrity. These improvements in complex I structure and function with Ran were associated with improved cardiac function after IR. However, these protective effects of Ran are not mediated by a direct action on mitochondria, but rather indirectly via cytosolic mechanisms that lead to less oxidation and better structural integrity of complex I.
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DOI：
10.1152/ajpheart.01032.2001
发表时间：
2002-06-01
影响因子：
4.8
作者：
Chen, Q;Camara, AKS;Stowe, DF
通讯作者：
Stowe, DF
影响因子：
5.5
作者：
Camara, Amadou K. S.;Aldakkak, Mohammed;Stowe, David F.
通讯作者：
Stowe, David F.
影响因子：
4.3
作者：
Grivennikova, Vera G.;Vinogradov, Andrei D.
通讯作者：
Vinogradov, Andrei D.
影响因子：
5.5
作者：
Aldakkak, Mohammed;Stowe, David F.;Camara, Amadou K. S.
通讯作者：
Camara, Amadou K. S.
影响因子：
4.8
作者：
Carroll, J;Shannon, RJ;Hirst, J
通讯作者：
Hirst, J