Elevated cytosolic Na+ increases mitochondrial formation of reactive oxygen species in failing cardiac myocytes.
Elevated cytosolic Na+ increases mitochondrial formation of reactive oxygen species in failing cardiac myocytes.
复制标题
DOI：
10.1161/circulationaha.109.914911
复制
发表时间：
2010-04-13
期刊：
影响因子：
37.8
通讯作者：
Maack C
中科院分区：
文献类型：
--
作者：
Kohlhaas M;Liu T;Knopp A;Zeller T;Ong MF;Böhm M;O'Rourke B;Maack C
氧化应激与心力衰竭的进展有因果关系，线粒体是衰竭心肌中活性氧的重要来源。我们之前观察到，在心力衰竭中，升高的细胞质Na+ ([Na+]i)通过加速Ca2+通过线粒体Na+/Ca2+交换器的外排来减少线粒体Ca2+ ([Ca2+]m)。由于抗氧化酶的再生需要NADPH，而NADPH是通过克雷布斯循环间接再生的，而克雷布斯循环脱氢酶被[Ca2+]m激活，我们推测在衰竭的肌细胞中，升高的[Na+]i促进了氧化应激。我们使用基于膜片钳的方法同时监测豚鼠心肌细胞的细胞质和线粒体Ca2+，或者线粒体H2O2和NAD(P)H。在电压箝位模式（3hz）下，细胞去极化，β-肾上腺素能刺激诱导负荷过渡。在这个转变过程中，NAD(P)H最初被氧化，但当[Ca2+]m增加时恢复。NAD(P)H的瞬时氧化与线粒体H2O2形成的增加密切相关。当线粒体Ca2+摄取被阻断（通过Ru360）或Ca2+外排加速（通过升高[Na+]i）时，这种活性氧的形成被增强。在衰竭的肌细胞中，H2O2的形成增加，这是通过线粒体Na+/Ca2+交换器减少线粒体Ca2+外排来阻止的。-除了匹配能量供需外，线粒体Ca2+摄取对线粒体活性氧的产生也有重要的调节作用。在心力衰竭中，升高的[Na+]i通过减少线粒体Ca2+的摄取来促进活性氧的形成。这种新的机制，通过离子平衡缺陷诱导氧化应激，代表了一个潜在的药物靶点，以减少衰竭心脏中活性氧的产生。
—Oxidative stress is causally linked to the progression of heart failure, and mitochondria are critical sources of reactive oxygen species in failing myocardium. We previously observed that in heart failure, elevated cytosolic Na+ ([Na+]i) reduces mitochondrial Ca2+ ([Ca2+]m) by accelerating Ca2+ efflux via the mitochondrial Na+/Ca2+ exchanger. Because the regeneration of antioxidative enzymes requires NADPH, which is indirectly regenerated by the Krebs cycle, and Krebs cycle dehydrogenases are activated by [Ca2+]m, we speculated that in failing myocytes, elevated [Na+]i promotes oxidative stress. —We used a patch-clamp–based approach to simultaneously monitor cytosolic and mitochondrial Ca2+ and, alternatively, mitochondrial H2O2 together with NAD(P)H in guinea pig cardiac myocytes. Cells were depolarized in a voltage-clamp mode (3 Hz), and a transition of workload was induced by β-adrenergic stimulation. During this transition, NAD(P)H initially oxidized but recovered when [Ca2+]m increased. The transient oxidation of NAD(P)H was closely associated with an increase in mitochondrial H2O2 formation. This reactive oxygen species formation was potentiated when mitochondrial Ca2+ uptake was blocked (by Ru360) or Ca2+ efflux was accelerated (by elevation of [Na+]i). In failing myocytes, H2O2 formation was increased, which was prevented by reducing mitochondrial Ca2+ efflux via the mitochondrial Na+/Ca2+ exchanger. —Besides matching energy supply and demand, mitochondrial Ca2+ uptake critically regulates mitochondrial reactive oxygen species production. In heart failure, elevated [Na+]i promotes reactive oxygen species formation by reducing mitochondrial Ca2+ uptake. This novel mechanism, by which defects in ion homeostasis induce oxidative stress, represents a potential drug target to reduce reactive oxygen species production in the failing heart.