Loss of interstitial collagen causes structural and functional alterations of cardiomyocyte subsarcolemmal mitochondria in acute volume overload.
Loss of interstitial collagen causes structural and functional alterations of cardiomyocyte subsarcolemmal mitochondria in acute volume overload.
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DOI：
10.1016/j.yjmcc.2010.10.034
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发表时间：
2011-01
影响因子：
5
通讯作者：
Dell'italia LJ
中科院分区：
文献类型：
--
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
下腔静脉瘘（ACF）引起的容量超负荷（VO）与氧化/炎症应激有关。由此产生的炎症、基质金属蛋白酶（MMP）活化和胶原降解被认为在左心室（LV）扩张和衰竭中起关键作用。由于线粒体也是炎症和氧化应激的靶点，我们假设急性VO会有生物能量功能障碍。在接受24小时ACF的Sprague-Dawley大鼠中，体内LV压力-容积面积增加了两倍，这与LV心肌氧利用增加和心肌细胞生物能量需求增加一致。从ACF LV分离的心肌细胞表现出增加过氧化氢和超氧化物的形成和增加MMP活性。肌膜下线粒体（SSM）显示状态3呼吸减少40%，SSM的蛋白质组学分析表明ACF中复合物I-V的水平降低。免疫组化分析显示，在ACF的SSM网络的肌膜下的位置中断。为了测试SSM功能障碍和间质胶原损失之间的潜在联系，在ACF之前用MMP抑制剂PD 166793处理大鼠。MMP-抑制剂保留了间质胶原、整合素-α5和SSM结构排列。此外，PD 166793阻止了ACF导致的状态3线粒体呼吸降低。这些研究确定了急性VO间质胶原降解与SSM结构和功能破坏之间的重要相互作用，这可能导致心力衰竭的进展。
Volume overload (VO) caused by aortocaval fistula (ACF) is associated with oxidative/inflammatory stress. The resulting inflammation, matrix metalloproteinase (MMP) activation, and collagen degradation is thought to play a pivotal role in left ventricular (LV) dilatation and failure. Since mitochondria are also targets for inflammation and oxidative stress, we hypothesized that there would be bioenergetic dysfunction with acute VO. In Sprague-Dawley rats subjected to 24 hrs of ACF, there was a two-fold increase in LV pressure-volume area in vivo, consistent with increased LV myocardial oxygen usage and increased bioenergetic demand in cardiomyocytes. Isolated cardiomyocytes from ACF LVs demonstrated increased hydrogen peroxide and superoxide formation and increased MMP activity. Subsarcolemmal mitochondria (SSM) showed a 40% decrease in state 3 respiration and proteomic analysis of SSM demonstrated decreased levels of complexes I-V in ACF. Immunohistochemical analysis revealed disruption of the subsarcolemmal location of the SSM network in ACF. To test for a potential link between SSM dysfunction and loss of interstitial collagen, rats were treated with the MMP-inhibitor PD166793 prior to ACF. MMP-inhibitor preserved interstitial collagen, integrin-α5 and the SSM structural arrangement. In addition, the decrease in state 3 mitochondrial respiration with ACF was prevented by PD166793. These studies established an important interaction between degradation of interstitial collagen in acute VO and the disruption of SSM structure and function which could contribute to progression to heart failure.
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影响因子：
30.8
作者：
Irwin, WA;Bergamin, N;Bonaldo, P
通讯作者：
Bonaldo, P
影响因子：
7.4
作者：
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通讯作者：
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影响因子：
3
作者：
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Delage, JP
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影响因子：
7.8
作者：
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通讯作者：
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影响因子：
9.5
作者：
Frantz, Stefan;Hu, Kai;Bauersachs, Johann
通讯作者：
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