Uncoupling of increased cellular oxidative stress and myocardial ischemia reperfusion injury by directed sarcolemma stabilization.
Uncoupling of increased cellular oxidative stress and myocardial ischemia reperfusion injury by directed sarcolemma stabilization.
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DOI：
10.1016/j.yjmcc.2013.12.008
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发表时间：
2014-02
影响因子：
5
通讯作者：
Metzger, Joseph M.
中科院分区：
文献类型：
--
作者：
Martindale, Joshua J.;Metzger, Joseph M.
心肌缺血再灌注（I/R）损伤是导致心功能障碍和心肌细胞死亡的主要临床问题。广泛认为I/R引起膜磷脂损伤，是心脏I/R损伤的重要机制。然而，I/R中肌层损伤的分子解剖很难通过实验来解决。我们在此研究了肌膜完整性增加或丧失条件下的心脏I/R损伤。为了在I/R过程中实现肌膜的完整性，合成的基于共聚物的肌膜稳定剂（CSS），包括Poloxamer 188 (P188)，被用作直接稳定肌膜的工具。与肌膜稳定假说一致，在未处理的肌细胞中明显的坏死和凋亡细胞标志物在肌膜稳定的肌细胞中被完全阻断。出乎意料的是，在两项独立的试验中，成人心肌细胞的肌层稳定并不影响心肌细胞产生的氧化剂或脂质过氧化的状态。我们还使用两种独立的遗传小鼠模型，dystrophin-deficient mdx或dysferlin敲除（Dysf KO）小鼠，研究了肌层完整性的丧失。体外I/R损伤对两种模型的肌上皮功能丧失都有严重影响，而CSS减轻了这种影响。体内研究也表明，css处理的心脏梗死面积显著减小。从机制上讲，这些发现支持I/ r介导的心肌细胞氧化应激增加与心肌细胞损伤分离的模型。由于这里使用的肌膜稳定剂不会穿过肌细胞膜，这证明当合成稳定剂保存肌膜的完整性时，细胞内氧化剂的靶标不会被充分改变而影响细胞死亡。这些发现反过来表明，肌膜不稳定和随之而来的Ca2+处理不当是心肌I/R损伤的局灶性启动机制。
Myocardial ischemia/reperfusion (I/R) injury is a major clinical problem leading to cardiac dysfunction and myocyte death. It is widely held that I/R causes damage to membrane phospholipids, and is a significant mechanism of cardiac I/R injury. Molecular dissection of sarcolemmal damage in I/R, however, has been difficult to address experimentally. We studied here cardiac I/R injury under conditions targeting gain- or loss-of sarcolemma integrity. To implement gain-in-sarcolemma integrity during I/R, synthetic copolymer-based sarcolemmal stabilizers (CSS), including Poloxamer 188 (P188), were used as a tool to directly stabilize the sarcolemma. Consistent with the hypothesis of sarcolemmal stabilization, cellular markers of necrosis and apoptosis evident in untreated myocytes were fully blocked in sarcolemma stabilized myocytes. Unexpectedly, sarcolemmal stabilization of adult cardiac myocytes did not affect the status of myocyte-generated oxidants or lipid peroxidation in two independent assays. We also investigated the loss of sarcolemmal integrity using two independent genetic mouse models, dystrophin-deficient mdx or dysferlin knockout (Dysf KO) mice. Both models of sarcolemmal loss-of-function were severely affected by I/R injury ex vivo, and this was lessened by CSS. In vivo studies also showed that infarct size was significantly reduced in CSS-treated hearts. Mechanistically, these findings support a model whereby I/R-mediated increased myocyte oxidative stress is uncoupled from myocyte injury. Because the sarcolemma stabilizers used here do not transit across the myocyte membrane this is evidence that intracellular targets of oxidants are not sufficiently altered to affect cell death when sarcolemma integrity is preserved by synthetic stabilizers. These findings, in turn, suggest that sarcolemma destabilization, and consequent Ca2+ mishandling, as a focal initiating mechanism underlying myocardial I/R injury.
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