title: Genetic deletion of uncoupling protein 3 exaggerates apoptotic cell death in the ischemic heart leading to heart failure.
abstract: BACKGROUND
  Uncoupling protein 3 (ucp3) is a member of the mitochondrial anion carrier superfamily of proteins uncoupling mitochondrial respiration. In this study, we investigated the effects of ucp3 genetic deletion on mitochondrial function and cell survival under low oxygen conditions in vitro and in vivo.
  
  
  RESULTS
  To test the effects of ucp3 deletion in vitro, murine embryonic fibroblasts and adult cardiomyocytes were isolated from wild-type (WT, n=67) and ucp3 knockout mice (ucp3(-/-), n=70). To test the effects of ucp3 genetic deletion in vivo, myocardial infarction (MI) was induced by permanent coronary artery ligation in WT and ucp3(-/-) mice. Compared with WT, ucp3(-/-) murine embryonic fibroblasts and cardiomyocytes exhibited mitochondrial dysfunction and increased mitochondrial reactive oxygen species generation and apoptotic cell death under hypoxic conditions in vitro (terminal deoxynucleotidyl transferase-dUTP nick end labeling-positive nuclei: WT hypoxia, 70.3 ± 1.2%; ucp3(-/-) hypoxia, 85.3 ± 0.9%; P<0.05). After MI, despite similar areas at risk in the 2 groups, ucp3(-/-) hearts demonstrated a significantly larger infarct size compared with WT (infarct area/area at risk: WT, 48.2 ± 3.7%; ucp3(-/-), 65.0 ± 2.9%; P<0.05). Eight weeks after MI, cardiac function was significantly decreased in ucp3(-/-) mice compared with WT (fractional shortening: WT MI, 42.7 ± 3.1%; ucp3(-/-) MI, 24.4 ± 2.9; P<0.05), and this was associated with heightened apoptotic cell death (terminal deoxynucleotidyl transferase-dUTP nick end labeling-positive nuclei: WT MI, 0.7 ± 0.04%; ucp3(-/-) MI, 1.1 ± 0.09%, P<0.05).
  
  
  CONCLUSIONS
  Our data indicate that ucp3 levels regulate reactive oxygen species levels and cell survival during hypoxia, modulating infarct size in the ischemic heart.
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Perrino
authors.forename: Gabriele G
authors.initials: GG
authors.lastname: Schiattarella
authors.forename: Anna
authors.initials: A
authors.lastname: Sannino
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Pironti
authors.forename: Maria Piera
authors.initials: MP
authors.lastname: Petretta
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cannavo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gargiulo
authors.forename: Federica
authors.initials: F
authors.lastname: Ilardi
authors.forename: Fabio
authors.initials: F
authors.lastname: Magliulo
authors.forename: Anna
authors.initials: A
authors.lastname: Franzone
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Carotenuto
authors.forename: Federica
authors.initials: F
authors.lastname: Serino
authors.forename: Giovanna G
authors.initials: GG
authors.lastname: Altobelli
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cimini
authors.forename: Alberto
authors.initials: A
authors.lastname: Cuocolo
authors.forename: Assunta
authors.initials: A
authors.lastname: Lombardi
authors.forename: Fernando
authors.initials: F
authors.lastname: Goglia
authors.forename: Ciro
authors.initials: C
authors.lastname: Indolfi
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D017353:Gene Deletion; D006333:Heart Failure / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics*; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics*; D017202:Myocardial Ischemia / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071247:Uncoupling Protein 3
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3
keywords: cardiac remodeling; free radicals; mitochondria; uncoupling protein