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. 2011 Oct;58(4):696-703.
doi: 10.1161/HYPERTENSIONAHA.111.174128. Epub 2011 Aug 8.

AMP activated protein kinase-α2 regulates expression of estrogen-related receptor-α, a metabolic transcription factor related to heart failure development

Xinli Hu  1 , Xin Xu, Zhongbing Lu, Ping Zhang, John Fassett, Ying Zhang, Yi Xin, Jennifer L Hall, Benoit Viollet, Robert J Bache, Yimin Huang, Yingjie Chen
Affiliations

AMP activated protein kinase-α2 regulates expression of estrogen-related receptor-α, a metabolic transcription factor related to heart failure development

Xinli Hu et al. Hypertension. 2011 Oct.

Abstract

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-α (ERRα), but not peroxisome proliferator-activated receptor-γ coactivator 1α, 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 left ventricular 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 knockout decreased myocardial ERRα (both mRNA and protein) and its downstream targets under basal conditions, with no change in myocardial peroxisome proliferator-activated receptor-γ coactivator 1α 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, overexpression of ERRα in AMPKα2 knockout 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.

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Figures

Figure 1
Figure 1
Expression of ERRα and energy metabolism related enzymes in failing human hearts. Western blots of human heart tissue samples (A). Myocardial ERRα was significantly decreased in the failing heart, which this was associated with decreases in some mitochondrial enzymes (B). * p< 0.05 as compared with normal donor hearts.
Figure 2
Figure 2
LV function and expression of myocardial ERRα and energy metabolism related enzymes in mice after TAC. Wild type mice were subjected to TAC for 2 or 4 weeks, which caused gradual deterioration of LV function (A–D) and reduction of myocardial ERRα and some mitochondrial enzymes (E,F). * p<0.05 as compared with control mice; # p<0.05 as compared with mice after 2 weeks of TAC.
Figure 3
Figure 3
Protein levels of myocardial ERRα and energy metabolism related enzymes in wild type and AMPKα2 deficient mice. Protein levels were determined by Western blots (A). Protein levels of ERRα and some energy metabolism related enzymes were significantly decreased in the AMPKα2 deficient mice (B). * p<0.05 as compared with wild type mice.
Figure 4
Figure 4
Alterations of ERRα, MCAD and CPT1b in rat neonatal cardiac myocytes in response to selective gene silencing of AMPKα2 or overexpression of constitutively active AMPKα. siRNA knockdown of AMPKα2 repressed the expression of ERRα, MCAD and CPT1 (A), while constitutively active AMPK increased expression of these proteins (C). * p<0.05 as compared with control siRNA transfected cells (B); or cells infected with adenovirus over expressing GFP (D).
Figure 5
Figure 5
AMPK regulates ERRα promoter activity. ERRα promoter activity was measured in rat neonatal cardiac myocytes transfected with ERR-promoter-luciferase constructs. ERRα promoter activity was increased after treatment with AICAR in a dose dependent manner (A). Inhibition of AMPKα2 expression by specific siRNA repressed ERRα promoter activity and its activation by AICAR (B). The reporter activity of serial deletions of ERRα promoter and their responses to AICAR induction (C). ChIP assay demonstrated that AICAR enhanced Sp1 binding to ERRα promoter in cardiac myocytes (D). Gene silencing of Sp1 by specific siRNA repressed ERRα promoter activity (E) and ERRα expression (F) at basal conditions, and attenuated their induction in response to AICAR. * p<0.05 as compared with vehicle treated cells; # p<0.05 as compared with non-specific siRNA transfected cells.
Figure 6
Figure 6
mRNA levels of MCAD, VLCAD and CPT1b in wild type and AMPKα2 deficient mouse neonatal cardiac myocytes after overexpression of constitutively active AMPKα2 or ERRα. Wild type and AMPKα2 deficient neonatal cardiac myocytes were infected with adenovirus expressing constitutively active AMPKα2 or ERRα. mRNA levels of MCAD, VLCAD and CPT1b were determined by RT and qPCR. Over-expression of constitutively active AMPKα2 or ERRα partially rescued expression of MCAD, VLCAD and CPT1b in AMPKα2 deficient neonatal cardiac myocytes. * p<0.05 as compared with cells infected with GFP adenovirus. # p<0.05 as compared with wild type cells.
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