Transient upregulation of PGC-1alpha diminishes cardiac ischemia tolerance via upregulation of ANT1.
Transient upregulation of PGC-1alpha diminishes cardiac ischemia tolerance via upregulation of ANT1.
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DOI：
10.1016/j.yjmcc.2010.06.008
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发表时间：
2010-10
影响因子：
5
通讯作者：
Sack MN
中科院分区：
文献类型：
--
作者：
Lynn EG;Stevens MV;Wong RP;Carabenciov D;Jacobson J;Murphy E;Sack MN
线粒体生物发生调节转录辅激活因子PGC-1α的长期心脏过表达破坏心脏收缩功能，其基因消融限制了心脏增强工作负荷的能力。相反，PGC-1α的瞬时诱导减轻了神经元细胞的氧化应激并增强了骨骼肌管的抗氧化防御。我们探讨了PGC-1α在心脏中的瞬时上调是否对缺血再灌注损伤具有保护作用。在心脏限制性诱导型PGC-1α转基因小鼠中瞬时诱导PGC-1α，使PGC-1α蛋白水平增加5倍。在Langendorff灌注装置上缺血25分钟和再灌注2小时后，与对照组相比，过表达PGC-1α的小鼠的收缩恢复和速率压力乘积显著减弱。亲和素基因阵列分析显示PGC-1α介导的腺嘌呤核苷酸移位酶1（ANT 1）上调3倍。由于ANT 1上调诱导心肌细胞死亡，我们研究了PGC-1α诱导ANT 1是否有助于这种增强的缺血应激敏感性。携带PGC-1α的腺病毒感染心脏来源的H9 c2细胞显著上调ANT 1而不改变基底细胞活力。在缺氧-复氧损伤的反应中，PGC-1α过表达后细胞死亡显著增加。这种有害作用在ANT 1的siRNA敲低后消除。类似地，在PGC-1α过表达的情况下ANT-1的减弱保持了响应过氧化氢应激的线粒体膜电位。有趣的是，单独敲除ANT 1也保护H9 c2细胞免受缺氧-复氧损伤。总之，这些数据表明，在小鼠心脏中瞬时诱导PGC-1α降低了H9 c2细胞的缺血-再灌注收缩恢复，并降低了缺氧-复氧耐受性。这些不良表型似乎部分由PGC-1α诱导的ANT 1上调介导。
Prolonged cardiac overexpression of the mitochondrial biogenesis regulatory transcriptional coactivator PGC-1α disrupts cardiac contractile function and its genetic ablation limits cardiac capacity to enhance work-load. In contrast, transient induction of PGC-1α alleviates neuronal cell oxidative stress and enhances skeletal myotube antioxidant defenses. We explored whether transient upregulation of PGC-1α in the heart protects against ischemia-reperfusion injury. The transient induction of PGC-1α in the cardiac-restricted inducible PGC-1α transgenic mouse, increased PGC-1α protein levels 5-fold. Following 25 minutes of ischemia and 2 hours of reperfusion on a Langendorff perfusion apparatus, contractile recovery and the rate pressure product was significantly blunted in mice overexpressing PGC-1α vs. controls. Affymetrix gene array analysis showed a 3-fold PGC-1α-mediated upregulation of adenine nucleotide translocase 1 (ANT1). As ANT1 upregulation induces cardiomyocyte cell death we investigated whether the induction of ANT1 by PGC-1α contributes to this enhanced ischemia-stress susceptibility. Infection with adenovirus harboring PGC-1α into cardiac-derived H9c2 cells significantly upregulates ANT1 without changing basal cell viability. In response to anoxia-reoxygenation injury cell death is significantly increased following PGC-1α overexpression. This detrimental effect is abolished following siRNA knockdown of ANT1. Similarly, the attenuation of ANT-1 in the presence of PGC-1α overexpression preserves the mitochondrial membrane potential in response to hydrogen-peroxide stress. Interestingly, the isolated knockdown of ANT1 also protects H9c2 cells from anoxia-reoxygenation injury. Taken together these data suggest that transient induction of PGC-1α in the murine heart decreases ischemia-reperfusion contractile recovery and diminishes anoxia-reoxygenation tolerance in H9c2 cells. These adverse phenotypes appear to be mediated, in part, by PGC-1α induced upregulation of ANT1.
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