title: Cardiomyocyte specific peroxisome proliferator-activated receptor-α overexpression leads to irreversible damage in ischemic murine heart.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor (PPAR)-α is downregulated in ischemic myocardium resulting in substrate switch from fatty acid oxidation to glucose utilization. Pharmacological PPAR-α activation leads to increased fatty acid oxidation and myocardial lipotoxicity. The aim of our study was to investigate the role of cardiomyocyte specific PPAR-α overexpression in myocardial adaptation to repetitive ischemic injury without myocardial infarction.
  
  
  METHODS
  Repetitive, brief I/R was performed in male and female MHC-PPAR-α overexpressing and wildtype-C57/Bl6 (WT)-mice, age 10-12 weeks, for 3 and 7 consecutive days. After echocardiography, their hearts were excised for histology and gene/protein-expression measurements (Taqman/Western blot).
  
  
  RESULTS
  MHC-PPAR-α mice developed microinfarctions already after 3 days of repetitive I/R in contrast to interstitial fibrosis in WT-mice. We found higher deposition of glycogen, increased apoptosis and dysfunctional regulation of antioxidative mediators in MHC-PPAR-α mice. MHC-PPAR-α mice presented with maladaptation of myosin heavy chain isoforms and worse left ventricular dysfunction than WT-mice. We found prolonged, chemokine-driven macrophage infiltration without induction of proinflammatory cytokines in MHC-PPAR-α mice. Persistent accumulation of myofibroblasts in microinfarctions indicated active remodeling resulting in scar formation in contrast to interstitial fibrosis without microinfarctions in WT-mice. However, MHC-PPAR-α hearts had only a weak induction of tenascin-C in contrast to its strong expression in WT-hearts.
  
  
  CONCLUSIONS
  Cardiomyocyte-specific PPAR-α overexpression led to irreversible cardiomyocyte loss with deteriorated ventricular function during brief, repetitive I/R episodes. We identified higher glycogen deposition, increased apoptosis, deranged antioxidative capacity and maladaptation of contractile elements as major contributors involved in the modulation of post-ischemic inflammation and remodeling.
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Electronic address: daniel.duerr@ukb.uni-bonn.de.
authors.forename: Georg D
authors.initials: GD
authors.lastname: Duerr
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Heinemann
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Arnoldi
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Feisst
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Kley
authors.affiliation: Department of Cardiology, Pneomology and Angiology - Medizinische Klinik II, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ghanem
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Welz
authors.affiliation: Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Dewald
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D047493:PPAR alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D047493:PPAR alpha
keywords: Apoptosis; Chemokines; Diabetes; Inflammation; Ischemia/reperfusion; PPAR-α; Remodeling