Modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in the rat.
Modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in the rat.
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DOI：
10.1371/journal.pone.0021285
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Sharma AC
中科院分区：
文献类型：
--
作者：
Chopra M;Golden HB;Mullapudi S;Dowhan W;Dostal DE;Sharma AC
我们测试了假设，5-羟基癸酸（5 HD），一个假定的mitoKATP通道阻滞剂，将逆转脓毒症诱导的心脏动力学和成年大鼠心室肌细胞（ARVM）收缩功能障碍，恢复线粒体膜通透性改变和改善生存。使用400 mg/kg盲肠接种物ip使雄性Sprague-Dawley大鼠（350-400 g）脓毒症。假手术动物接受5%葡萄糖水，ip。在从假手术和脓毒症大鼠心脏获得的分离的单个ARVM中测定电压依赖性阴离子通道（VDAC 1）、Bax和细胞色素C水平。在存在/不存在5 HD（100 µ mol）的情况下，从用去甲肾上腺素（NE，10 µ mol）处理的ARVM中分离线粒体和胞质组分。在诱导脓毒症时（−40%）和脓毒症后6小时（−20%），使用Alzet泵连续输注5 HD可逆转脓毒症诱导的死亡率。心电图显示，5 HD逆转了脓毒症引起的平均射血分数下降，双腔+M模式（脓毒症组53.5±2.5，脓毒症+5 HD组24小时69.2±1.2，基础组79.9±1.5）和心输出量（脓毒症+5 HD组中脓毒症为63.3±1.2 mL/min，24 h时为79.3±3.9 mL/min，基础组为85.8±1.5 mL/min）。用5 HD治疗ARVM还逆转了溶媒组和NE治疗组中脓毒症诱导的收缩性抑制。脓毒症导致VDAC 1显著下调，Bax水平上调，沿着ARVM中线粒体膜电位崩溃。用5 HD预处理脓毒症ARVM可阻断NE诱导的VDAC 1减少和细胞色素C释放。这些数据表明，Bax激活是一个上游事件，可能先于开放的mitoKATP通道脓毒症。我们的结论是，通过降低线粒体膜电位和减少细胞色素C的释放mitoKATP通道抑制提供了对脓毒症诱导的ARVM和心肌收缩功能障碍的保护。
We tested the hypothesis that 5-Hydroxydecanoic acid (5HD), a putative mitoKATP channel blocker, will reverse sepsis-induced cardiodynamic and adult rat ventricular myocyte (ARVM) contractile dysfunction, restore mitochondrial membrane permeability alterations and improve survival. Male Sprague-Dawley rats (350–400 g) were made septic using 400 mg/kg cecal inoculum, ip. Sham animals received 5% dextrose water, ip. The Voltage Dependent Anion Channels (VDAC1), Bax and cytochrome C levels were determined in isolated single ARVMs obtained from sham and septic rat heart. Mitochondria and cytosolic fractions were isolated from ARVMs treated with norepinephrine (NE, 10 µmoles) in the presence/absence of 5HD (100 µmoles). A continuous infusion of 5HD using an Alzet pump reversed sepsis-induced mortality when administered at the time of induction of sepsis (−40%) and at 6 hr post-sepsis (−20%). Electrocardiography revealed that 5HD reversed sepsis-induced decrease in the average ejection fraction, Simpsons+m Mode (53.5±2.5 in sepsis and 69.2±1.2 at 24 hr in sepsis+5HD vs. 79.9±1.5 basal group) and cardiac output (63.3±1.2 mL/min sepsis and 79.3±3.9 mL/min at 24 hr in sepsis+5HD vs. 85.8±1.5 mL/min basal group). The treatment of ARVMs with 5HD also reversed sepsis-induced depressed contractility in both the vehicle and NE-treated groups. Sepsis produced a significant downregulation of VDAC1, and upregulation of Bax levels, along with mitochondrial membrane potential collapse in ARVMs. Pretreatment of septic ARVMs with 5HD blocked a NE-induced decrease in the VDAC1 and release of cytochrome C. The data suggest that Bax activation is an upstream event that may precede the opening of the mitoKATP channels in sepsis. We concluded that mitoKATP channel inhibition via decreased mitochondrial membrane potential and reduced release of cytochrome C provided protection against sepsis-induced ARVM and myocardial contractile dysfunction.
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影响因子：
5
作者：
Gupta, A;Aberle, NS;Sharma, AC
通讯作者：
Sharma, AC
影响因子：
3
作者：
Bernardi, P;Petronilli, V
通讯作者：
Petronilli, V
DOI：
10.1152/ajpregu.00432.2003
发表时间：
2004-03-01
影响因子：
2.8
作者：
Brealey, D;Karyampudi, S;Singer, M
通讯作者：
Singer, M
影响因子：
56.9
作者：
Hiller, Sebastian;Garces, Robert G.;Wagner, Gerhard
通讯作者：
Wagner, Gerhard
影响因子：
4.3
作者：
Brahmbhatt, S;Gupta, A;Sharma, A
通讯作者：
Sharma, A