title: Activation of mitochondrial function and Hb expression in non-haematopoietic cells by an EPO inducer ameliorates ischaemic diseases in mice.
abstract: OBJECTIVE
  Many organs suffer from ischaemic injuries that reduce their ability to generate sufficient energy, which is required for functional maintenance and repair. Erythropoietin (EPO) ameliorates ischaemic injuries by pleiotropic effects. The aim of this study was to investigate the effect and mechanism of a small molecule EH-201, and found it as a potent EPO inducer and its effect in non-haematopoietic cells for therapeutic potential in ischemic disorders.
  
  
  METHODS
  Mice kidney slices, primary hepatocytes, primary cardiomyocytes and C2C12 myoblasts were treated with EH-201. The effects of this treatment on EPO, Hb expression and mitochondrial biogenesis were analysed. In vivo, doxorubicin-induced cardiomyopathic mice were treated with EH-201. The mice were subjected to an endurance test, electrocardiography and echocardiography, and a histological examination of the isolated hearts was performed. EH-201 was also administered to cisplatin-induced nephropathic mice.
  
  
  RESULTS
  In non-haematopoietic cells, EH-201 was potent at inducing EPO. EH-201 also stimulated mitochondrial biogenesis and enhanced the expression of Hb by a mechanism dependent on EPO-mediated signalling. In mechanistic studies, using EPO and EPO receptor-neutralizing antibodies, we confirmed that EH-201 enhances EPO-EPOR autocrine activity. EH-201 robustly increased the endurance performance activity of healthy and cardiomyopathic mice during hypoxic stress, enhanced myocardial mitochondrial biogenesis and Hb expression, and also improved cardiac function. EH-201 ameliorated anaemia and renal dysfunction in nephropathic mice.
  
  
  CONCLUSIONS
  The enhancement and recovery of cellular functions through the stimulation of mitochondrial activity and Hb production in non-haematopoietic cells by an inducer of endogenous EPO has potential as a therapeutic strategy for ischaemic diseases.
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Pei-Lun
authors.initials: PL
authors.lastname: Hsu
authors.forename: Lin-Yea
authors.initials: LY
authors.lastname: Horng
authors.forename: Kang-Yung
authors.initials: KY
authors.lastname: Peng
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Wu
authors.forename: Hui-Ching
authors.initials: HC
authors.lastname: Sung
authors.forename: Rong-Tsun
authors.initials: RT
authors.lastname: Wu
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004921:Erythropoietin / Q000819:agonists* / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology*; D057809:HEK293 Cells; D006454:Hemoglobins / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000819:agonists*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D005960:Glucosides; D006454:Hemoglobins; D017467:Receptors, Erythropoietin; D013267:Stilbenes; D004921:Erythropoietin; C093026:2,3,5,4'-tetrahydroxystilbene 2-O-glucopyranoside; D004317:Doxorubicin; D002945:Cisplatin
keywords: anaemia; cardiomyopathy; endurance performance; erythropoietin; haemoglobin; inducer; ischaemic disease; mitochondria; non-haematopoietic cell