Monoamine oxidase A-mediated enhanced catabolism of norepinephrine contributes to adverse remodeling and pump failure in hearts with pressure overload.
Monoamine oxidase A-mediated enhanced catabolism of norepinephrine contributes to adverse remodeling and pump failure in hearts with pressure overload.
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DOI：
10.1161/circresaha.109.198366
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发表时间：
2010-01-08
影响因子：
20.1
通讯作者：
Paolocci N
中科院分区：
文献类型：
--
作者：
Kaludercic N;Takimoto E;Nagayama T;Feng N;Lai EW;Bedja D;Chen K;Gabrielson KL;Blakely RD;Shih JC;Pacak K;Kass DA;Di Lisa F;Paolocci N
单胺氧化酶(MAO)是一种线粒体酶，能分解代谢去甲肾上腺素和5-羟色胺等促肥大神经递质，产生过氧化氢。由于过量的活性氧(ROS)和儿茶酚胺是充血性心力衰竭的主要病理生理因素，MAO可能在这一过程中发挥重要作用。在这里，我们研究了MAO-A在适应性不良肥厚和心力衰竭中的作用。我们报道，在NE刺激下，分离的新生儿和成人心肌细胞中MAO-A活性被触发，随后细胞大小增加，ROS产生，并出现不适应性肥大的迹象。所有这些体外变化部分独立于α和β肾上腺素能受体操作的信号，并被特定的MAO-A抑制剂Clorgyline抑制。在因压力超负荷导致左心室(LV)扩张和泵衰竭的小鼠中，MAO-A对NE的分解代谢增加，并伴随着加剧的氧化应激。抑制MAO-A可以阻止这些改变，并逆转胎儿基因重新编程、金属蛋白酶和caspase-3的激活以及心肌细胞的凋亡。在表达显性负MAO-A(MAO-Aneo)的小鼠身上进一步测试了MAO-A的特定作用，这些小鼠比它们的野生型小鼠更能抵御压力超负荷。除了肾上腺素能受体依赖的机制外，MAO-A活性的增强和心肌内NE可获得性的增加导致ROS的产生增加，从而导致慢性应激心脏的不良适应性重构和左心功能障碍。
Monoamine oxidases (MAO) are mitochondrial enzymes that catabolize pro-hypertrophic neurotransmitters such as norepinephrine and serotonin, generating hydrogen peroxide. Since excess reactive oxygen species (ROS) and catecholamines are major contributors to the pathophysiology of congestive heart failure, MAO could play an important role in this process. Here we investigated the role of MAO-A in maladaptive hypertrophy and heart failure. We report that MAO-A activity is triggered in isolated neonatal and adult myocytes upon stimulation with NE, followed by increase in cell size, ROS production, and signs of maladaptive hypertrophy. All these in vitro changes occur in part independently from α- and β-adrenergic receptor-operated signaling and are inhibited by the specific MAO-A inhibitor clorgyline. In mice with left ventricular (LV) dilation and pump failure due to pressure overload, NE catabolism by MAO-A is increased accompanied by exacerbated oxidative stress. MAO-A inhibition prevents these changes, and also reverses fetal gene re-programming, metalloproteinase and caspase-3 activation as well as myocardial apoptosis. The specific role of MAO-A was further tested in mice expressing a dominant-negative MAO-A (MAO-Aneo), which were more protected against pressure overload than their wild type littermates. In addition to adrenergic receptor-dependent mechanisms, enhanced MAO-A activity coupled with increased intramyocardial NE availability results in increased ROS generation, contributing to maladaptive remodeling and LV dysfunction in hearts subjected to chronic stress.