Potential role of BNIP3 in cardiac remodeling, myocardial stiffness, and endoplasmic reticulum: mitochondrial calcium homeostasis in diastolic and systolic heart failure.
Potential role of BNIP3 in cardiac remodeling, myocardial stiffness, and endoplasmic reticulum: mitochondrial calcium homeostasis in diastolic and systolic heart failure.
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DOI：
10.1161/circheartfailure.112.000200
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发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
Hajjar RJ
中科院分区：
文献类型：
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作者：
Chaanine AH;Gordon RE;Kohlbrenner E;Benard L;Jeong D;Hajjar RJ
我们已经表明 BNIP3 表达在心力衰竭中显着增加。在这项研究中，我们测试了 BNIP3 操作对心衰的影响。在压力超负荷心力衰竭大鼠模型中，BNIP3 敲低可显着降低左心室容积，并显着改善左心室舒张和收缩功能。心肌细胞凋亡和左心室间质纤维化显着减少。从超微结构上看，BNIP3 敲低减弱了线粒体断裂并恢复了线粒体形态和完整性。在分子水平上，内质网应激和线粒体凋亡标记物显着减少。 BNIP3介导线粒体功能障碍的机制之一是通过VDAC通道的寡聚化，导致钙从内质网转移到线粒体室，导致内质网钙含量减少、线粒体损伤、细胞凋亡和左室间质纤维化，从而分别导致收缩期和舒张期心肌功能障碍。在收缩期心力衰竭中，与 SERCA2a 表达正常的舒张期心力衰竭相比，SERCA2a 的下调以及 BNIP3 表达的增加，进一步恶化了心肌舒张和收缩功能，并导致收缩期心力衰竭中出现的主要重构。 BNIP3表达的增加主要通过线粒体凋亡、左心室间质纤维化导致心肌舒张功能障碍，并在一定程度上由于钙从内质网转移到线粒体以及内质网钙含量减少而导致心肌收缩功能障碍。然而，SERCA2a 下调仍然是收缩性心力衰竭中出现主要左室重塑的先决条件。
We have shown that BNIP3 expression is significantly increased in HF. In this study, we tested the effects of BNIP3 manipulation in HF. In a rat model of pressure overload HF, BNIP3 knockdown significantly decreased LV volumes with significant improvement in LV diastolic and systolic function. There were significant decreases in myocardial apoptosis and LV interstitial fibrosis. Ultrastructurally, BNIP3 knockdown attenuated mitochondrial fragmentation and restored mitochondrial morphology and integrity. On the molecular level there were significant decreases in ER stress and mitochondrial apoptotic markers. One of the mechanisms by which BNIP3 mediates mitochondrial dysfunction is via the oligomerization of the VDAC channels causing a shift of calcium from the ER to mitochondrial compartments leading to the decrease in ER calcium content, mitochondrial damage, apoptosis and LV interstitial fibrosis and hence contributes to both systolic and diastolic myocardial dysfunction, respectively. In systolic HF, the downregulation of SERCA2a, along with an increased BNIP3 expression, further worsen myocardial diastolic and systolic function and contribute to the major remodeling seen in systolic HF as compared to diastolic HF with normal SERCA2a expression. The increase in BNIP3 expression contributes mainly to myocardial diastolic dysfunction through mitochondrial apoptosis, LV interstitial fibrosis and to some extent to myocardial systolic dysfunction due to the shift of calcium from the ER to the mitochondria and to the decrease in ER calcium content. However, SERCA2a downregulation remains a prerequisite for the major LV remodeling seen in systolic HF.