AMPK isoform expression in the normal and failing hearts.
AMPK isoform expression in the normal and failing hearts.
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DOI：
10.1016/j.yjmcc.2012.01.016
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发表时间：
2012-05
影响因子：
5
通讯作者：
Tian R
中科院分区：
文献类型：
--
作者：
Kim M;Shen M;Ngoy S;Karamanlidis G;Liao R;Tian R
AMP激活的蛋白激酶(AMPK)是一种主要的代谢开关，在细胞和全身水平的能量平衡中起着重要的作用，因此是一个很有前途的药物靶点。AMPK是由催化的α亚基和调节的β和γ亚基组成的异三聚体复合体，每个亚基有多种异构体。已有研究表明，在心肌肥厚和衰竭时，AMPK活性增加，但目前尚不清楚AMPK亚基组成的变化是否与AMPK活性改变有关。在这项研究中，我们测定了AMPK亚基亚型在小鼠心脏发育过程中以及在心肌肥大和心力衰竭过程中的蛋白表达模式。我们还将小鼠心脏衰竭的结果与人类心脏衰竭的结果进行了比较，以确定小鼠心脏是否是人类疾病中AMPK的良好模型。在小鼠发育心脏中，AMPK在胎儿期高度表达，出生后回落至成体水平。在衰竭小鼠心脏中，α-2、β-2和γ-2亚基在基因和蛋白水平均显著增加。相反，我们发现在衰竭心脏中α-1、β-1和γ-2c亚基的蛋白水平显著增加，而其基因水平没有变化。我们还比较了小鼠和人类衰竭心脏中异构体特异性AMPK的活性。与文献一致，在衰竭的小鼠心脏中，α-2复合体占总AMPK活性的2/3，而α-1复合体占剩余的30-35%。然而，在人的心脏中，α1-AMPK活性的贡献在非心力衰竭的心脏中显著更高(40%)，在心力衰竭的心脏中进一步增加到50%。因此，与啮齿动物心脏相比，人类心脏具有更多的α1-AMPK活性。综上所述，在正常发育和心力衰竭过程中，心脏中AMPK的蛋白水平和亚型分布发生了显著的变化。这些观察结果为未来针对AMPK的治疗策略的发展提供了基础。
AMP-activated protein kinase (AMPK) is a master metabolic switch that plays an important role in energy homeostasis at the cellular and whole body level, hence a promising drug target. AMPK is a heterotrimeric complex composed of catalytic α-subunit and regulatory β- and γsubunits with multiple isoforms for each subunit. It has been shown that AMPK activity is increased in cardiac hypertrophy and failure but it is unknown whether changes in subunit composition of AMPK contribute to the altered AMPK activity. In this study, we determined the protein expression pattern of AMPK subunit isoforms during cardiac development as well as during cardiac hypertrophy and heart failure in mouse heart. We also compared the findings in failing mouse heart to that of the human failing hearts in order to determine whether the mouse heart is a good model of AMPK in human diseases. In mouse developmental hearts, AMPK was highly expressed in the fetal stages and fell back to the adult level after birth. In the failing mouse heart, there was a significant increase in α2, β2, and γ2 subunits both at the mRNA and protein levels. In contrary, we found significant increases in the protein level of α1, β1 and γ2c subunits in human failing hearts with no change in the mRNA level. We also compared isoform-specific AMPK activity in the mouse and human failing hearts. Consistent with the literature, in the failing mouse heart, the α2 complexes accounted for ~2/3 of total AMPK activity while the α1 complexes accounted for the remaining 30–35%. In the human hearts, however, the contribution of α1-AMPK activity were significantly higher (>40%) in the non-failing hearts, and it further increased to 50% in the failing hearts. Thus, the human hearts have a greater amount of α1-AMPK activity compared to the rodent hearts. In summary, the protein level and the isoform distribution of AMPK in the heart change significantly during normal development as well as in heart failure. These observations provide a basis for future development of therapeutic strategies for targeting AMPK.
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影响因子：
11.8
作者：
Dasgupta, Biplab;Milbrandt, Jeffrey
通讯作者：
Milbrandt, Jeffrey
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.0705070104
发表时间：
2007-07-17
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
5.5
作者：
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