title: Loss of myocardial LIF receptor in experimental heart failure reduces cardiotrophin-1 cytoprotection. A role for neurohumoral agonists?
abstract: OBJECTIVE
  Cardiomyocyte loss is involved in the transition from compensatory left ventricular hypertrophy (LVH) to heart failure (HF). Our aim was to investigate the status of the leukaemia inhibitory factor receptor (LIFR)/gp130 survival pathway and its cytoprotective activity in intact cardiac tissue and in cardiomyocytes obtained from adult spontaneously hypertensive rats (SHR) with LVH (non-failing SHR) and from aged SHR with overt HF (failing SHR).
  
  
  METHODS
  Cardiac morphometry was assayed by planimetry in an image analysis system. mRNA and protein expression were quantified by real time RT-PCR and Western blotting. Receptors were localized by immunocytochemistry. Trypan blue staining, TUNEL, and MTT cell viability assays were employed to study the cytoprotective activity of cardiotrophin-1 (CT-1) in isolated caridomyocytes.
  
  
  RESULTS
  Compared to non-failing SHR, failing SHR exhibited enhanced myocardial cell death (p<0.01) demonstrated by the increase in Bax/Bcl-2 ratio, caspase-3 activation and poly (ADP-ribose) polymerase (PARP) fragmentation. Failing SHR had a 7-fold diminished expression (p<0.01) of LIFR, no changes in gp130, and 1.6-fold increased myocardial expression (p<0.01) of CT-1. In cardiomyocytes isolated from non-failing SHR, recombinant CT-1 inhibited apoptotic and non-apoptotic cell death induced by angiotensin II or hydrogen peroxide. LIFR protein was entirely absent in cardiomyocytes isolated from failing SHR, which were resistant to the cytoprotective effects of CT-1. Finally, stimulation of non-failing SHR cardiomyocytes with angiotensin II, aldosterone, norepinephrine or endothelin-1 significantly decreased (p<0.01) LIFR expression.
  
  
  CONCLUSIONS
  These data suggest that loss of CT-1-dependent survival mechanisms may contribute to the increase of cell death associated with HF in SHR. Neurohumoral activation may contribute to this alteration via suppression of LIFR.
authors.affiliation: Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: López
authors.forename: Nerea
authors.initials: N
authors.lastname: Varo
authors.forename: Javier
authors.initials: J
authors.lastname: Díez
authors.forename: María Antonia
authors.initials: MA
authors.lastname: Fortuño
mesh_terms: D000450:Aldosterone / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D019610:Cytoprotection; D019332:Endothelin-1 / Q000494:pharmacology; D006333:Heart Failure / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D053606:Receptors, OSM-LIF / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016207:Cytokines; D019332:Endothelin-1; D053605:Leukemia Inhibitory Factor; D012333:RNA, Messenger; D053606:Receptors, OSM-LIF; D000804:Angiotensin II; D000450:Aldosterone; C092073:cardiotrophin 1; D009638:Norepinephrine