Molecular and structural transition mechanisms in long-term volume overload.
Molecular and structural transition mechanisms in long-term volume overload.
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DOI：
10.1002/ejhf.465
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发表时间：
2016-04
影响因子：
18.2
通讯作者：
Toischer, Karl
中科院分区：
文献类型：
--
作者：
Mohamed, Belal A.;Schnelle, Moritz;Khadjeh, Sara;Lbik, Dawid;Herwig, Melissa;Linke, Wolfgang A.;Hasenfuss, Gerd;Toischer, Karl
我们以前曾报道，实验性容量超负荷(VO)的早期阶段(1 周)具有适应性表型，而室壁应力匹配压力超负荷(PO)是不适应性的。在这里，我们研究了长期VO从适应到心力衰竭(HF)的转变。FVB/N野生型小鼠经主-腔分流术建立VO模型后，行连续超声心动图检查，直至在体左室射血分数低于50%(135 ± 35 d)。与假手术组相比，心力衰竭明显表现为肺和肝重量增加和死亡率增加。适应性不良的重塑导致肌节肌动蛋白磷酸化显著降低(导致肌节硬度增加)，而间质纤维化并未增加。与此平行的是胎儿基因程序的重新表达，钙/钙调蛋白依赖的蛋白激酶II(CaMKII)的激活，蛋白激酶B(Akt)的磷酸化降低，高氧化应激，以及增加细胞凋亡。在Akt缺乏的小鼠中，心力衰竭的发展和死亡率一直显著加重。VO向HF的转变与Akt降低和CaMKII信号通路增加以及氧化应激和细胞凋亡增加有关。在VO诱导的HF中，间质纤维化的缺乏和肌节肌动蛋白的低磷酸化表明肌节但不是基质水平的僵硬增加(与PO相反)。过渡到HF可能是由于僵硬增加导致的肌细胞丢失和肌细胞功能障碍。
We have previously reported that early phase (1 week) of experimental volume overload (VO) has an adaptive phenotype while wall stress‐matched pressure overload (PO) is maladaptive. Here we investigate the transition from adaptation to heart failure (HF) in long‐term VO. FVB/N wild‐type mice were subjected to VO induced by aortocaval shunt, and were followed by serial echocardiography until in vivo left ventricular ejection fraction was below <50% (135 ± 35 days). Heart failure was evident from increased lung and liver weight and increased mortality compared with sham. Maladaptive remodelling resulted in significantly reduced sarcomeric titin phosphorylation (causing increased sarcomeric stiffness), whereas interstitial fibrosis was not increased. This was paralleled by re‐expression of the fetal gene program, activation of calcium/calmodulin‐dependent protein kinase II (CaMKII), decreased protein kinase B (Akt) phosphorylation, high oxidative stress, and increased apoptosis. Consistently, development of HF and mortality were significantly aggravated in Akt‐deficient mice. Transition to HF in VO is associated with decreased Akt and increased CaMKII signalling pathways together with increased oxidative stress and apoptosis. Lack of interstitial fibrosis together with sarcomeric titin hypophosphorylation indicates an increased stiffness at the sarcomeric but not matrix level in VO‐induced HF (in contrast to PO). Transition to HF may result from myocyte loss and myocyte dysfunction owing to increased stiffness.
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影响因子：
5
作者：
Ulasova E;Gladden JD;Chen Y;Zheng J;Pat B;Bradley W;Powell P;Zmijewski JW;Zelickson BR;Ballinger SW;Darley-Usmar V;Dell'italia LJ
通讯作者：
Dell'italia LJ
影响因子：
37.8
作者：
Toischer K;Rokita AG;Unsöld B;Zhu W;Kararigas G;Sossalla S;Reuter SP;Becker A;Teucher N;Seidler T;Grebe C;Preuss L;Gupta SN;Schmidt K;Lehnart SE;Krüger M;Linke WA;Backs J;Regitz-Zagrosek V;Schäfer K;Field LJ;Maier LS;Hasenfuss G
通讯作者：
Hasenfuss G
影响因子：
20.1
作者：
Hidalgo C;Hudson B;Bogomolovas J;Zhu Y;Anderson B;Greaser M;Labeit S;Granzier H
通讯作者：
Granzier H
影响因子：
20.1
作者：
Hamdani, Nazha;Krysiak, Judith;Linke, Wolfgang A.
通讯作者：
Linke, Wolfgang A.
影响因子：
15.9
作者：
Wencker, D;Chandra, M;Kitsis, RN
通讯作者：
Kitsis, RN