Melatonin maintains mitochondrial membrane potential and attenuates activation of initiator (casp-9) and effector caspases (casp-3/casp-7) and PARP in UVR-exposed HaCaT keratinocytes
Melatonin maintains mitochondrial membrane potential and attenuates activation of initiator (casp-9) and effector caspases (casp-3/casp-7) and PARP in UVR-exposed HaCaT keratinocytes
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DOI：
10.1111/j.1600-079x.2007.00542.x
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发表时间：
2008-05-01
影响因子：
10.3
通讯作者：
Slominski, A.
中科院分区：
文献类型：
--
作者：
Fischer, T. W.;Zmijewski, M. A.;Slominski, A.
褪黑激素是一种公认的抗氧化剂，在与氧化应激相关的许多疾病中具有很高的保护作用，如神经退行性疾病、缺血/再灌注综合征、败血症和衰老。褪黑激素通过其自由基清除特性和/或抗凋亡活性可能有利地影响这些过程。此外，越来越多的证据表明，褪黑激素的这些作用可能与角质形成细胞有关，角质形成细胞是皮肤的主要细胞群，它有助于保护免受紫外线辐射（UVR）引起的损伤。因此，我们研究了紫外线诱导的角质形成细胞凋亡的动力学特征的形态和线粒体的变化，半胱天冬酶依赖的凋亡途径和参与的聚（ADP-核糖）聚合酶（PARP）的激活，以及褪黑激素的保护作用。当用UVB辐射（50 mJ/cm（2））照射时，与照射的非褪黑激素处理的对照组相比，褪黑激素处理的培养角质形成细胞更融合，显示更少的细胞起泡，更均匀的形状和更少的核凝聚。与褪黑激素预孵育也导致正常化的降低紫外线诱导的线粒体膜电位。这些褪黑激素的影响，其次是抑制线粒体通路相关的启动caspase-9（casp-9）的激活，但不是死亡受体依赖的casp-8后24和48小时UVR曝光。褪黑激素在UV照射后24-48小时下调效应器半胱天冬酶（casp-3/casp-7），并在24小时减少PARP活化。因此，褪黑激素在UV照射的角质形成细胞中特别活跃，维持线粒体膜电位，抑制内在凋亡途径的连续活化并减少PARP活化。总之，这些数据提供了详细的证据，具体的抗凋亡机制的褪黑激素在紫外线诱导的人角质形成细胞的损伤。
Melatonin is a recognized antioxidant with high potential as a protective agent in many conditions related to oxidative stress such as neurodegenerative diseases, ischemia/reperfusion syndromes, sepsis and aging. These processes may be favorably affected by melatonin through its radical scavenging properties and/or antiapoptotic activity. Also, there is increasing evidence that these effects of melatonin could be relevant in keratinocytes, the main cell population of the skin where it would contribute to protection against damage induced by ultraviolet radiation (UVR). We therefore investigated the kinetics of UVR-induced apoptosis in cultured keratinocytes characterizing the morphological and mitochondrial changes, the caspases-dependent apoptotic pathways and involvement of poly(ADP-ribose) polymerase (PARP) activation as well as the protective effects of melatonin. When irradiated with UVB radiation (50 mJ/cm(2)), melatonin treated, cultured keratinocytes were more confluent, showed less cell blebbing, more uniform shape and less nuclear condensation as compared to irradiated, nonmelatonin-treated controls. Preincubation with melatonin also led to normalization of the decreased UVR-induced mitochondrial membrane potential. These melatonin effects were followed by suppression of the activation of mitochondrial pathway-related initiator caspase 9 (casp-9), but not of death receptor-dependent casp-8 between 24 and 48 hr after UVR exposure. Melatonin down-regulated effector caspases (casp-3/casp-7) at 24-48 hr post-UV irradiation and reduced PARP activation at 24 hr. Thus, melatonin is particularly active in UV-irradiated keratinocytes maintaining the mitochondrial membrane potential, inhibiting the consecutive activation of the intrinsic apoptotic pathway and reducing PARP activation. In conclusion, these data provide detailed evidence for specific antiapoptotic mechanisms of melatonin in UVR-induced damage of human keratinocytes.