Bianchi Pascale, Kunduzova Oxana, Masini Emanuela, Cambon Claudie, Bani Daniele, Raimondi Laura, Seguelas Marie-Helene, Nistri Silvia, Colucci Wilson, Leducq Nathalie, Parini Angelo
INSERM U388, 31432 Toulouse Cedex 4, France.
Circulation. 2005 Nov 22;112(21):3297-305. doi: 10.1161/CIRCULATIONAHA.104.528133. Epub 2005 Nov 14.
Serotonin (5-hydroxytryptamine [5-HT]), released by activated platelets during cardiac ischemia, is metabolized by the mitochondrial enzyme monoamine oxidase A (MAO-A). Because hydrogen peroxide is one of the byproducts of 5-HT degradation by MAO-A, we investigated the potential role of reactive oxygen species generated by MAOs in 5-HT-dependent cardiomyocyte death and post-ischemia-reperfusion cardiac damage.
Treatment of isolated adult rat cardiomyocytes with 5-HT induced intracellular oxidative stress and cell apoptosis. The apoptotic cascade triggered by 5-HT involves release of cytochrome c, upregulation of proapoptotic Bax protein, and downregulation of antiapoptotic Bcl-2 protein. These effects were prevented by inhibition of amine transporter or MAO, antioxidants, or iron chelation. In contrast, cardiomyocyte apoptosis was only slightly affected by the 5-HT(2B) receptor antagonist SB 206553. In vivo, inhibition of MAO-A largely reduced myocardial ultrastructural damage induced by 30 minutes of ischemia followed by 60 minutes of reperfusion in the rat heart. Cardioprotective effects of MAO inhibitors were associated with the prevention of postischemic oxidative stress, neutrophil accumulation, and mitochondrial-dependent cell death and were not reverted by SB 206553. Administration of MAO-A inhibitors during ischemia was still effective in preventing cardiac damage.
Our results supply the first direct evidence that oxidative stress induced by MAO is responsible for receptor-independent apoptotic effects of 5-HT in cardiomyocytes and postischemic myocardial injury. These findings provide new insight into the mechanisms of 5-HT action in the heart and may constitute the basis for novel therapies.
心脏缺血期间活化血小板释放的血清素（5-羟色胺[5-HT]）由线粒体酶单胺氧化酶A（MAO-A）代谢。由于过氧化氢是MAO-A降解5-HT的副产物之一，我们研究了MAO产生的活性氧在5-HT依赖性心肌细胞死亡和缺血后再灌注心脏损伤中的潜在作用。
用5-HT处理分离的成年大鼠心肌细胞可诱导细胞内氧化应激和细胞凋亡。5-HT触发的凋亡级联反应涉及细胞色素c的释放、促凋亡Bax蛋白的上调和抗凋亡Bcl-2蛋白的下调。抑制胺转运体或MAO、抗氧化剂或铁螯合可预防这些效应。相比之下，5-HT(2B)受体拮抗剂SB 206553对心肌细胞凋亡的影响较小。在体内，抑制MAO-A可大大减轻大鼠心脏30分钟缺血后再灌注60分钟所诱导的心肌超微结构损伤。MAO抑制剂的心脏保护作用与预防缺血后氧化应激、中性粒细胞积聚和线粒体依赖性细胞死亡有关，且不受SB 206553的影响。在缺血期间给予MAO-A抑制剂仍可有效预防心脏损伤。
我们的结果提供了首个直接证据，即MAO诱导的氧化应激是5-HT在心肌细胞中不依赖受体的凋亡效应及缺血后心肌损伤的原因。这些发现为5-HT在心脏中的作用机制提供了新的见解，并可能构成新疗法的基础。
