Regulation of fibre contraction in a rat model of myocardial ischemia.
Regulation of fibre contraction in a rat model of myocardial ischemia.
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DOI：
10.1371/journal.pone.0009528
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发表时间：
2010-03-04
期刊：
影响因子：
3.7
通讯作者：
Ogut O
中科院分区：
文献类型：
--
作者：
Han YS;Ogut O
肌动球蛋白过桥周期的变化是心脏收缩性改变的基础，尽管它们对设计合理的治疗方法很重要，但尚未得到很好的描述。采用大鼠缺血-再灌注模型测定缺血时影响的过桥周期的转变。与灌注心脏相比，缺血心脏纤维的每横截面积最大力和Ca2+敏感性均降低。Ca2+和ATP的光解释放激活了肌肉，这表明收缩力的改变最好描述为非循环肌动球蛋白过桥激活到激活循环状态的激活率的降低。更具体地说，是无受力a - m - adp之间过渡的正向表观速率常数。Pi状态与约束，受力AM*. adp。缺血纤维的Pi状态降低，表明这种转变与最初的交叉桥激活是相称的。这些结果表明，细丝调节单元的激活与初始交叉桥连接之间的关系发生了变化，促使人们对肌钙蛋白（Tn） T和i的翻译后状态进行了研究。这些分析表明，缺血期间，TnT的二磷酸化形式减少，同时TnI的Ser23/24磷酸化水平降低。用8-Br-cAMP处理灌注纤维增加了TnI的Ser23/24磷酸化，改变了Pi异构化的反向速率常数，这与β-肾上腺素能刺激的致肥作用一致。然而，缺血纤维的类似处理并未改变TnI磷酸化或Pi异构化动力学。缺血减少了a - m.d adp的异构化。Pi到AM*. adp。Pi，通过可能由改变的TnT和TnI磷酸化介导的机制改变交叉桥激活动力学。
The changes in the actomyosin crossbridge cycle underlying altered contractility of the heart are not well described, despite their importance to devising rational treatment approaches. A rat ischemia–reperfusion model was used to determine the transitions of the crossbridge cycle impacted during ischemia. Compared to perfused hearts, the maximum force per cross-sectional area and Ca2+ sensitivity of fibers from ischemic hearts were both reduced. Muscle activation by photolytic release of Ca2+ and ATP suggested that the altered contractility was best described as a reduction in the rate of activation of noncycling actomyosin crossbridges to activated, cycling states. More specifically, the apparent forward rate constant of the transition between the nonforce bearing A-M.ADP.Pi state and the bound, force bearing AM*.ADP.Pi state was reduced in ischemic fibers, suggesting that this transition is commensurate with initial crossbridge activation. These results suggested an alteration in the relationship between the activation of thin filament regulatory units and initial crossbridge attachment, prompting an examination of the post-translational state of troponin (Tn) T and I. These analyses indicated a reduction in the diphosphorylated form of TnT during ischemia, along with lower Ser23/24 phosphorylation of TnI. Treatment of perfused fibers by 8-Br-cAMP increased Ser23/24 phosphorylation of TnI, altering the reverse rate constant of the Pi isomerization in a manner consistent with the lusitropic effect of β-adrenergic stimulation. However, similar treatment of ischemic fibers did not change TnI phosphorylation or the kinetics of the Pi isomerization. Ischemia reduces the isomerization from A-M.ADP.Pi to AM*.ADP.Pi, altering the kinetics of crossbridge activation through a mechanism that may be mediated by altered TnT and TnI phosphorylation.