title: Lactate up-regulates the expression of lactate oxidation complex-related genes in left ventricular cardiac tissue of rats.
abstract: BACKGROUND
  Besides its role as a fuel source in intermediary metabolism, lactate has been considered a signaling molecule modulating lactate-sensitive genes involved in the regulation of skeletal muscle metabolism. Even though the flux of lactate is significantly high in the heart, its role on regulation of cardiac genes regulating lactate oxidation has not been clarified yet. We tested the hypothesis that lactate would increase cardiac levels of reactive oxygen species and up-regulate the expression of genes related to lactate oxidation complex.
  
  
  RESULTS
  Isolated hearts from male adult Wistar rats were perfused with control, lactate or acetate (20mM) added Krebs-Henseleit solution during 120 min in modified Langendorff apparatus. Reactive oxygen species (O2●-/H2O2) levels, and NADH and NADPH oxidase activities (in enriched microsomal or plasmatic membranes, respectively) were evaluated by fluorimetry while SOD and catalase activities were evaluated by spectrophotometry. mRNA levels of lactate oxidation complex and energetic enzymes MCT1, MCT4, HK, LDH, PDH, CS, PGC1α and COXIV were quantified by real time RT-PCR. Mitochondrial DNA levels were also evaluated. Hemodynamic parameters were acquired during the experiment. The key findings of this work were that lactate elevated cardiac NADH oxidase activity but not NADPH activity. This response was associated with increased cardiac O2●-/H2O2 levels and up-regulation of MCT1, MCT4, LDH and PGC1α with no changes in HK, PDH, CS, COXIV mRNA levels and mitochondrial DNA levels. Lactate increased NRF-2 nuclear expression and SOD activity probably as counter-regulatory responses to increased O2●-/H2O2.
  
  
  CONCLUSIONS
  Our results provide evidence for lactate-induced up-regulation of lactate oxidation complex associated with increased NADH oxidase activity and cardiac O2●-/H2O2 driving to an anti-oxidant response. These results unveil lactate as an important signaling molecule regulating components of the lactate oxidation complex in cardiac muscle.
authors.affiliation: School of physical Education and Sport, University of São Paulo, São Paulo, Brazil.
authors.forename: Daniele
authors.initials: D
authors.lastname: Gabriel-Costa
authors.affiliation: School of physical Education and Sport, University of São Paulo, São Paulo, Brazil.
authors.forename: Telma Fatima
authors.initials: TF
authors.lastname: da Cunha
authors.affiliation: School of physical Education and Sport, University of São Paulo, São Paulo, Brazil.
authors.forename: Luiz Roberto Grassmann
authors.initials: LR
authors.lastname: Bechara
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Rodrigo Soares
authors.initials: RS
authors.lastname: Fortunato
authors.affiliation: School of physical Education and Sport, University of São Paulo, São Paulo, Brazil.
authors.forename: Luiz Henrique Marchesi
authors.initials: LH
authors.lastname: Bozi
authors.affiliation: School of physical Education and Sport, University of São Paulo, São Paulo, Brazil.
authors.forename: Marcele de Almeida
authors.initials: Mde A
authors.lastname: Coelho
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Maria Luiza
authors.initials: ML
authors.lastname: Barreto-Chaves
authors.affiliation: School of physical Education and Sport, University of São Paulo, São Paulo, Brazil.
authors.forename: Patricia Chakur
authors.initials: PC
authors.lastname: Brum
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism*; D006439:Hemodynamics; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D015854:Up-Regulation; D016276:Ventricular Function
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D009243:NAD; D019344:Lactic Acid; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D019255:NADPH Oxidases