Activation of PPARβ/δ protects cardiac myocytes from oxidative stress-induced apoptosis by suppressing generation of reactive oxygen/nitrogen species and expression of matrix metalloproteinases
Activation of PPARβ/δ protects cardiac myocytes from oxidative stress-induced apoptosis by suppressing generation of reactive oxygen/nitrogen species and expression of matrix metalloproteinases
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DOI：
10.1016/j.phrs.2015.03.008
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发表时间：
2015-05-01
影响因子：
9.3
通讯作者：
Lazou, Antigone
中科院分区：
文献类型：
--
作者：
Barlaka, Eleftheria;Goerbe, Aniko;Lazou, Antigone
心力衰竭仍然是全球发病率和死亡率的主要原因之一。一个主要的因素是活性氧/氮物种(RON)的过度产生，它与心脏重塑有关，部分是通过心肌细胞凋亡。过氧化物酶体增殖物激活受体(PPAR)是一类配体激活的转录因子，属于核受体超家族，具有心脏保护作用。然而，其分子机制在很大程度上还没有被探索。在这项研究中，我们试图研究在过氧化氢诱导的成年大鼠心肌细胞氧化应激的背景下，激活PPARβ/Delta所引起的潜在的有益效应。选择性PPARβ/Delta激动剂GW0742可抑制H_2O_2诱导的细胞凋亡，提高细胞存活率。此外，在PPARβ/Delta激动剂存在的情况下，心肌细胞中RONS的产生被减弱。这些效应在PPARβ/Delta拮抗剂存在时被取消，表明其作用是通过PPARβ/Delta受体激活实现的。PPARβ/Delta激动剂还可抑制caspase-3和PARP的裂解，上调抗凋亡基因Bcl2，下调促凋亡基因Bax的表达。此外，PPARβ/Delta的激活抑制了氧化应激诱导的基质金属蛋白酶-2和基质金属蛋白酶-9的mRNA表达上调。结论：PPARβ/Delta激活通过抑制氧化应激、基质金属蛋白酶表达和细胞凋亡，对氧化应激大鼠心肌细胞具有细胞保护作用。我们的数据表明，PPAR信号与心肌细胞中基质金属蛋白酶下调之间的新联系可能是治疗氧化应激所致心功能障碍的新靶点。(C)2015爱思唯尔有限公司。保留所有权利。
Heart failure still remains one of the leading causes of morbidity and mortality worldwide. A major contributing factor is reactive oxygen/nitrogen species (RONS) overproduction which is associated with cardiac remodeling partly through cardiomyocyte apoptosis. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear receptor superfamily and have been implicated in cardioprotection. However, the molecular mechanisms are largely unexplored. In this study we sought to investigate the potential beneficial effects evoked by activation of PPAR beta/delta under the setting of oxidative stress induced by H2O2 in adult rat cardiac myocytes. The selective PPAR beta/delta agonist GW0742 inhibited the H2O2-induced apoptosis and increased cell viability. In addition, generation of RONS was attenuated in cardiac myocytes in the presence of PPAR beta/delta agonist. These effects were abolished in the presence of the PPAR beta/delta antagonist indicating that the effect was through PPAR beta/delta receptor activation. Treatment with PPAR beta/delta agonist was also associated with attenuation of caspase-3 and PARP cleavage, upregulation of anti-apoptotic Bcl-2 and concomitant downregulation of pro-apoptotic Bax. In addition, activation of PPAR beta/delta inhibited the oxidative-stress-induced MMP-2 and MMP-9 mRNA upregulation. It is concluded that PPAR beta/delta activation exerts a cytoprotective effect in adult rat cardiac myocytes subjected to oxidative stress via inhibition of oxidative stress, MMP expression, and apoptosis. Our data suggest that the novel connection between PPAR signaling and MMP down-regulation in cardiac myocytes might represent a new target for the management of oxidative stress-induced cardiac dysfunction. (C) 2015 Elsevier Ltd. All rights reserved.