The nuclear receptor ERRα is required for the bioenergetic and functional adaptation to cardiac pressure overload
The nuclear receptor ERRα is required for the bioenergetic and functional adaptation to cardiac pressure overload
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DOI：
10.1016/j.cmet.2007.06.005
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发表时间：
2007-07-01
期刊：
影响因子：
29
通讯作者：
Kelly, Daniel P.
中科院分区：
文献类型：
--
作者：
Huss, Janice M.;Imahashi, Ken-ichi;Kelly, Daniel P.
转录辅激活因子PGC-1 α的下调和功能失活与心力衰竭的发病机制有关。我们假设雌激素相关受体α (ERR α)在已知导致心力衰竭的应激源的背景下发挥保护作用，该受体将PGC-1 α招募到心脏代谢靶基因。左心室压力过载的ERR α(-/-)小鼠表现出心力衰竭的特征，包括心室扩张和左室分数缩短减少。p -31核磁共振研究显示ERR α(-/-)心脏在血流动力学应激下的异常磷酸肌酸消耗，表明ATP储备缺陷。线粒体呼吸研究表明ERR α(-/-)心脏最大ATP合成率降低。参与能量底物氧化、ATP合成和磷酸盐转移的心脏ERR α靶基因在ERR α(-/-)小鼠基线或压力过载时下调。这些结果表明，核受体ERR α是对已知引起心力衰竭的血流动力学应激源的适应性生物能量反应所必需的。
Downregulation and functional deactivation of the transcriptional coactivator PGC-1 alpha has been implicated in heart failure pathogenesis. We hypothesized that the estrogen-related receptor alpha (ERR alpha), which recruits PGC-1 alpha to metabolic target genes in heart, exerts protective effects in the context of stressors known to cause heart failure. ERR alpha(-/-) mice subjected to left ventricular (LV) pressure overload developed signatures of heart failure including chamber dilatation and reduced LV fractional shortening. P-31-NMR studies revealed abnormal phosphocreatine depletion in ERR alpha(-/-) hearts subjected to hemodynamic stress, indicative of a defect in ATP reserve. Mitochondrial respiration studies demonstrated reduced maximal ATP synthesis rates in ERR alpha(-/-) hearts. Cardiac ERR alpha target genes involved in energy substrate oxidation, ATP synthesis, and phosphate transfer were downregulated in ERR alpha(-/-) mice at baseline or with pressure overload. These results demonstrate that the nuclear receptor ERR alpha is required for the adaptive bioenergetic response to hemodynamic stressors known to cause heart failure.