Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart.
Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart.
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DOI：
10.1161/circresaha.109.214353
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发表时间：
2010-06-11
影响因子：
20.1
通讯作者：
Piantadosi CA
中科院分区：
文献类型：
--
作者：
Carraway MS;Suliman HB;Jones WS;Chen CW;Babiker A;Piantadosi CA
Erythropoietin (EPO) is often administered to cardiac patients with anemia, particularly from chronic kidney disease, and stimulation of erythropoiesis may stabilize left ventricular and renal function by recruiting protective effects beyond the correction of anemia. We examined the hypothesis that EPO receptor (EpoR) ligand-binding, which activates endothelial nitric oxide synthase (eNOS), regulates the pro-survival program of mitochondrial biogenesis in the heart. We investigated the effects of EPO on mitochondrial biogenesis over 14 days in healthy mice. Mice expressing a mitochondrial GFP-reporter construct demonstrated sharp increases in myocardial mitochondrial density post-EPO by 3 days that peaked at 7 days and surpassed hepatic or renal effects and anteceded significant increases in blood hemoglobin content. Quantitatively, in wild-type (Wt) mice, Complex II activity, State 3 respiration and mtDNA copy number increased significantly; also resting energy expenditure and natural running speed improved with no evidence of an increase in LV mass index. Mechanistically, EPO activated cardiac mitochondrial biogenesis by enhancement of nuclear respiratory factor-1 (NRF-1), PGC-1α and mitochondrial transcription factor-A gene expression in Wt, but not in eNOS-/- or Akt1-/- mice. EpoR was required, as EpoR silencing in cardiomyocytes blocked EPO-mediated nuclear translocation of NRF-1. These findings support a new physiological and protective role for EPO, acting through its cell surface receptor and eNOS-Akt1 signal transduction, in matching cardiac mitochondrial mass to the convective O2 transport capacity as erythrocyte mass expands.
