SIRT1 modulates MAPK pathways in ischemic-reperfused cardiomyocytes
SIRT1 modulates MAPK pathways in ischemic-reperfused cardiomyocytes
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DOI：
10.1007/s00018-012-0925-5
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发表时间：
2012-07-01
影响因子：
8
通讯作者：
Fiorillo, Claudia
中科院分区：
文献类型：
--
作者：
Becatti, Matteo;Taddei, Niccolo;Fiorillo, Claudia
SIRT 1是一种普遍存在的NAD（+）依赖性脱乙酰酶，在生物过程中发挥作用，如长寿和应激反应，在响应活性氧（ROS）产生时被显著激活。白藜芦醇（Resv）是SIRT 1的重要激活剂，已被证明在与氧化应激相关的疾病中发挥重要的健康益处。在缺血-再灌注（IR）损伤中，主要作用归因于丝裂原活化蛋白激酶（MAPK）途径，其响应于多种应激刺激（包括氧化应激）而上调。在模拟IR的乳鼠心室肌细胞中，研究Resv诱导的SIRT 1激活的作用及其与MAPK通路的关系。Resv诱导的SIRT 1过表达保护心肌细胞免受IR诱导的氧化损伤、线粒体功能障碍和细胞死亡。我们首次证明SIRT 1过表达通过减少p38和JNK磷酸化和增加ERK磷酸化，通过Akt/ASK 1信号传导对MAPK通路产生积极影响。这些结果揭示了IR组织中Resv诱导的SIRT 1激活引起的新的保护机制，并提出了管理IR诱导的心功能障碍的新的潜在治疗靶点。
SIRT1, an ubiquitous NAD(+)-dependent deacetylase that plays a role in biological processes such as longevity and stress response, is significantly activated in response to reactive oxygen species (ROS) production. Resveratrol (Resv), an important activator of SIRT1, has been shown to exert major health benefits in diseases associated with oxidative stress. In ischemia-reperfusion (IR) injury, a major role has been attributed to the mitogen-activated protein kinase (MAPK) pathway, which is upregulated in response to a variety of stress stimuli, including oxidative stress. In neonatal rat ventricular cardiomyocytes subjected to simulated IR, the effect of Resv-induced SIRT1 activation and the relationships with the MAPK pathway were investigated. Resv-induced SIRT1 overexpression protected cardiomyocytes from oxidative injury, mitochondrial dysfunction, and cell death induced by IR. For the first time, we demonstrate that SIRT1 overexpression positively affects the MAPK pathway-via Akt/ASK1 signaling-by reducing p38 and JNK phosphorylation and increasing ERK phosphorylation. These results reveal a new protective mechanism elicited by Resv-induced SIRT1 activation in IR tissues and suggest novel potential therapeutic targets to manage IR-induced cardiac dysfunction.