AMP activated protein kinase-α2 regulates expression of estrogen-related receptor-α, a metabolic transcription factor related to heart failure development.
AMP activated protein kinase-α2 regulates expression of estrogen-related receptor-α, a metabolic transcription factor related to heart failure development.
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DOI：
10.1161/hypertensionaha.111.174128
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发表时间：
2011-10
期刊：
影响因子：
--
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Hu X;Xu X;Lu Z;Zhang P;Fassett J;Zhang Y;Xin Y;Hall JL;Viollet B;Bache RJ;Huang Y;Chen Y
心肌线粒体酶的正常表达对维持心脏能量储备和促进应激反应至关重要，但维持心肌线粒体酶表达的分子机制尚不清楚。我们在此报道，在人心力衰竭样本中，充血性心力衰竭与心肌雌激素相关受体α（ERRα）显著降低相关，而与过氧化物酶体增殖物激活物γ辅激活因子-1 α（PGC 1 α）无关。此外，慢性压力超负荷可导致ERRα表达降低，并与左室功能不全、肺充血程度及一组心肌能量代谢相关基因表达降低显著相关。我们发现代谢传感器AMP激活的蛋白激酶（AMPK）在体内和体外调节ERRα的表达。AMPKα2 KO在基础条件下降低心肌ERRα（mRNA和蛋白）及其下游靶点，而心肌PGC 1 α表达无变化。利用培养的新生大鼠心肌细胞，我们发现组成性激活的AMPKα过表达显著诱导ERRα mRNA、蛋白和启动子活性。相反，AMPKα2的选择性基因沉默抑制ERRα及其靶基因水平，表明AMPKα2参与ERRα表达的调节。此外，ERRα在AMPKα2 KO新生心肌细胞中的过表达部分地挽救了一些能量代谢相关基因的表达抑制。这些数据支持AMPKα2在调节心肌ERRα及其下游线粒体酶的表达中的重要作用。
The normal expression of myocardial mitochondrial enzymes is essential to maintain the cardiac energy reserve and facilitate responses to stress, but the molecular mechanisms to maintain myocardial mitochondrial enzyme expression have been elusive. Here we report that congestive heart failure is associated with a significant decrease of myocardial Estrogen-Related Receptor alpha (ERRα), but not PPAR gamma coactivator-1 alpha (PGC1α), in human heart failure samples. In addition, chronic pressure overload in mice caused a decrease of ERRα expression that was significantly correlated to the degree of LV dysfunction, pulmonary congestion and decreases of a group of myocardial energy metabolism related genes. We found that the metabolic sensor AMP activated protein kinase (AMPK) regulates ERRα expression in vivo and in vitro. AMPKα2 KO decreased myocardial ERRα (both mRNA and protein) and its downstream targets under basal conditions, with no change in myocardial PGC1α expression. Using cultured rat neonatal cardiac myocytes, we found that overexpression of constitutively active AMPKα significantly induced ERRα mRNA, protein and promoter activity. Conversely, selective gene silencing of AMPKα2 repressed ERRα and its target gene levels, indicating that AMPKα2 is involved in the regulation of ERRα expression. In addition, over-expression of ERRα in AMPKα2 KO neonatal cardiac myocytes partially rescued the repressed expression of some energy metabolism related genes. These data support an important role for AMPKα2 in regulating the expression of myocardial ERRα and its downstream mitochondrial enzymes.