小鼠内毒素血症型心肌病的痊愈源于其心肌细胞胞内钙调控的上调
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Up-regulation of Intracellular Calcium Handling Underlies the Recovery of Endotoxemic Cardiomyopathy in Mice
背景与目的
罹患脓毒血症型心肌病的幸存者的心肌病能自发痊愈。通常认为脓毒血症心肌的痊愈可能与患者全身免疫反应的缓解有关，但并无相关的实验证据可以进行论证。本研究的目的是明确内毒素血症小鼠心肌损伤后复原的心肌方面机制。
方 法
雄性C57BL/6小鼠经腹腔注射脂多糖后继续饲养12天。记录此过程中小鼠的生存率，并分别观察超声心动图下小鼠心功能变化和离体心肌电刺激中肌节的缩短和胞内钙离子转运以及检测免疫印迹中心肌相关蛋白的表达情况。
结 果
注射脂多糖12h后的小鼠减少了左心室的射血分数和胞内钙离子的转运，同时也缩短了其心肌细胞肌节的缩短程度。但以上改变在24h时将逐渐缓解并在第三天时恢复至各项指标的基线水平。其中，第三天时钙转运的恢复与肌浆网钙泵上调至基线的139±19%和受磷蛋白下调至基线的35±20%水平有关。第六天时钙转运增加至基线的123±31%水平，可能与肌浆网钙负荷的增加（增至基线的126±32%水平，与咖啡因作用情况下检测的值相同）以及钠钙交换体的抑制（下降至基线的48±12%水平）有关。
结 论
脂多糖处理后幸存小鼠受损心肌收缩功能的自然恢复与高于基线水平的心肌胞内钙调控的上调有关，这提示心肌细胞复原过程中可能涉及肌浆网钙泵的激活和受磷蛋白的下调以及钠钙交换体的抑制。
原始文献摘要
Morse J C, Huang J, Khona N, et al. Up-regulation of Intracellular Calcium Handling Underlies the Recovery of Endotoxemic Cardiomyopathy in Mice.[J]. Anesthesiology, 2017,126(6):1125-1138. DOI:10.1097/ALN.0000000000001627
Background: In surviving patients, sepsis-induced cardiomyopathy is spontaneously reversible. In the absence of any experimental data, it is generally thought that cardiac recovery in sepsis simply follows the remission of systemic infammation. Here the authors aimed to identify the myocardial mechanisms underlyingcardiac recovery in endotoxemic mice.
Methods: Male C57BL/6 mice were challenged with lipopolysaccharide (7 μg/g, intraperitoneally) and followed for 12 days. Te authors assessed survival, cardiac function by echocardiography, sarcomere shortening, and calcium transients (with fura-2-acetoxymethyl ester) in electrically paced cardiomyocytes (5 Hz, 37oC) and myocardial protein expression by immunoblotting.
Results: Left ventricular ejection fraction, cardiomyocyte sarcomere shortening, and calcium transients were depressed 12 h after lipopolysaccharide challenge, started to recover by 24 h (day 1), and were back to baseline at day 3. Te recovery of calcium transients at day 3 was associated with the up-regulation of the sarcoplasmic reticulum calcium pump to 139 ± 19% (mean ± SD) of baseline and phospholamban down-regulation to 35 ± 20% of baseline. At day 6, calcium transients were increased to 123 ± 31% of baseline, associated with increased sarcoplasmic reticulum calcium load (to 126 ± 32% of baseline, as measured with cafeine) and inhibition of sodium/calcium exchange (to 48 ± 12% of baseline).
Conclusions: In mice surviving lipopolysaccharide challenge, the natural recovery of cardiac contractility was associated with the up-regulation of cardiomyocyte calcium handling above baseline levels, indicating the presence of an active myocardial recovery process, which included sarcoplasmic reticulum calcium pump activation, the down-regulation of phospholamban, and sodium/calcium exchange inhibition. (A 2017; 126:1125-38)。
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