BNip3 and signal-specific programmed death in the heart.
BNip3 and signal-specific programmed death in the heart.
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DOI：
10.1016/j.yjmcc.2004.11.007
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发表时间：
2005
影响因子：
5
通讯作者：
K. Webster;R. Graham;N. Bishopric
中科院分区：
文献类型：
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作者：
K. Webster;R. Graham;N. Bishopric
BH 3-only蛋白，包括BNip 3，是细胞死亡调节因子Bcl-2家族的成员。尽管蛋白质如Bax和巴克在大多数形式的细胞凋亡中起核心作用，但仅BH 3蛋白似乎通过细胞类型和信号特异性途径调节细胞凋亡。本文就BNip 3在缺血心肌细胞凋亡信号转导中的作用作一综述。我们最近发现，在高糖存在下的缺氧导致培养的心肌细胞进行性酸中毒。心肌细胞在中性pH下对慢性缺氧有抵抗力，但当[pH] o降至6.5以下时，心肌细胞会发生广泛的死亡。对20，000个基因的微阵列分析鉴定了促凋亡Bcl-2家族成员BNip 3是心肌细胞中>100个缺氧诱导基因中上调最强烈的基因之一。BNip 3 mRNA增加了12倍，BNip 3蛋白的6倍，在24小时的缺氧; BNip 3蛋白的积累进一步增强酸中毒。BNip 3在中性缺氧条件下与线粒体松散结合，但在酸性pH下与线粒体通透性转换孔（MPTP）的开放相一致。随后的DNA片段化和细胞死亡没有被半胱天冬酶抑制剂阻断，但被反义BNip 3寡核苷酸和MPTP抑制剂抑制，表明BNip 3激活了具有凋亡和坏死特征的非典型程序性死亡途径。缺氧和酸中毒对BNip 3的顺序诱导和激活为观察中性pH下慢性缺氧不促进新生心肌细胞凋亡或激活caspase提供了分子基础。
The BH3-only proteins, including BNip3, are members of the Bcl-2 family of cell death-regulating factors. Whereas proteins such as Bax and Bak play a central role in most forms of apoptosis, the BH3-only proteins appear to modulate apoptosis through cell type- and signal-specific pathways. This review will focus on our studies of the specific role of BNip3 in cardiac myocyte apoptotic signaling during ischemia. We recently showed that hypoxia in the presence of high glucose leads to progressive acidosis of cardiac myocytes in culture. Cardiac myocytes are resistant to chronic hypoxia at neutral pH but undergo extensive death when the [pH]odrops below 6.5. A micro-array analysis of 20,000 genes identified the pro-apoptotic Bcl-2 family member BNip3 as one of the most strongly upregulated of >100 hypoxia-inducible genes in cardiac myocytes. BNip3 mRNA increased by 12-fold, and BNip3 protein by sixfold, during 24 h of hypoxia; BNip3 protein accumulation was further enhanced by acidosis. BNip3 was loosely bound to mitochondria under conditions of neutral hypoxia but became more tightly associated at acid pH, coincident with opening of the mitochondrial permeability transition pore (MPTP). Subsequent DNA fragmentation and cell death were not blocked by caspase inhibitors, but were inhibited by antisense BNip3 oligonucleotides and MPTP inhibitors, indicating that BNip3 activates an atypical programmed death pathway with features of both apoptosis and necrosis. The sequential induction and activation of BNip3 by hypoxia and acidosis provide a molecular basis for the observation that chronic hypoxia at neutral pH does not promote apoptosis or activate caspases in neonatal cardiac myocytes.