Mitochondrial Integrity and Function in the Progression of Early Pressure Overload-Induced Left Ventricular Remodeling.
Mitochondrial Integrity and Function in the Progression of Early Pressure Overload-Induced Left Ventricular Remodeling.
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DOI：
10.1161/jaha.117.005869
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发表时间：
2017-06-15
影响因子：
5.4
通讯作者：
Redfield MM
中科院分区：
文献类型：
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作者：
Chaanine AH;Sreekumaran Nair K;Bergen RH 3rd;Klaus K;Guenzel AJ;Hajjar RJ;Redfield MM
在压力过载后，代偿性同心左心室重构（CR）可转变为偏心重构（ER）和收缩功能障碍。负责这种转变的机制还没有完全被理解。在这里，我们利用压力过载引起的心脏重塑的表型变异性来验证线粒体稳态和钙处理的改变发生在从CR到ER转变的早期，在明显的收缩功能障碍之前的假设。Sprague Dawley大鼠接受升主动脉束带（n=68）或假手术（n=5）。在升主动脉束带后3周，所有大鼠均显示CR（左心室容积<假手术）。在升主动脉束带后8周，射血分数增加或保留，但3种几何表型明显，尽管压力过载严重程度相似：持续性CR、轻度ER和中度ER，左心室容积分别低于、类似和高于假手术。与假手术相比，CR和轻度内质网表型表现出磷蛋白、S16磷酸化增加、钠钙交换剂表达减少、线粒体生物生成/含量增加和正常氧化能力增加，而中度内质网表型表现出对磷蛋白、S16表达减少、钠钙交换剂表达增加、线粒体生物生成/含量相似程度。线粒体自噬和凋亡标志物（BNIP3和Bax/Bcl‐2）的独特激活导致氧化能力受损。压力过载后，代偿性CR中线粒体的生物发生、功能和钙处理增强，向轻度ER的过渡与线粒体生物发生和含量的减少有关；然而，向中度内质网的进展与线粒体自噬/凋亡增强、线粒体功能和钙处理受损有关，这些都发生在明显的收缩功能障碍之前。
Following pressure overload, compensatory concentric left ventricular remodeling (CR) variably transitions to eccentric remodeling (ER) and systolic dysfunction. Mechanisms responsible for this transition are incompletely understood. Here we leverage phenotypic variability in pressure overload–induced cardiac remodeling to test the hypothesis that altered mitochondrial homeostasis and calcium handling occur early in the transition from CR to ER, before overt systolic dysfunction. Sprague Dawley rats were subjected to ascending aortic banding, (n=68) or sham procedure (n=5). At 3 weeks post–ascending aortic banding, all rats showed CR (left ventricular volumes < sham). At 8 weeks post–ascending aortic banding, ejection fraction was increased or preserved but 3 geometric phenotypes were evident despite similar pressure overload severity: persistent CR, mild ER, and moderate ER with left ventricular volumes lower than, similar to, and higher than sham, respectively. Relative to sham, CR and mild ER phenotypes displayed increased phospholamban, S16 phosphorylation, reduced sodium‐calcium exchanger expression, and increased mitochondrial biogenesis/content and normal oxidative capacity, whereas moderate ER phenotype displayed decreased p‐phospholamban, S16, increased sodium‐calcium exchanger expression, similar degree of mitochondrial biogenesis/content, and impaired oxidative capacity with unique activation of mitochondrial autophagy and apoptosis markers (BNIP3 and Bax/Bcl‐2). After pressure overload, mitochondrial biogenesis and function and calcium handling are enhanced in compensatory CR. The transition to mild ER is associated with decrease in mitochondrial biogenesis and content; however, the progression to moderate ER is associated with enhanced mitochondrial autophagy/apoptosis and impaired mitochondrial function and calcium handling, which precede the onset of overt systolic dysfunction.