title: Leptin signalling reduces the severity of cardiac dysfunction and remodelling after chronic ischaemic injury.
abstract: OBJECTIVE
  Leptin is elevated under conditions of both obesity and heart failure (HF), and activation of leptin receptor (ObR) signalling is known to increase in vivo cardiac contractility and to have anti-hypertrophic effects on the left ventricle (LV). However, it is unknown whether ObR signalling is altered in cardiomyocytes after myocardial infarction (MI) leading to HF, or if a deficiency in ObR signalling leads to worse HF.
  
  
  RESULTS
  In separate experimental protocols, C57BL/6J and leptin-deficient (ob/ob) mice underwent open-chest surgery to induce permanent left coronary artery ligation (CAL) or had a sham operation. Subgroups of ob/ob mice examined were lean (food-restricted), obese (food-ad libitum), and leptin repleted. Four weeks post-surgery, cardiac structure and function was examined by echocardiography, and the activation of cardiac leptin signalling was characterized through quantitative PCR, western blotting, and DNA-binding activities. CAL produced echocardiographic evidence of HF in C57BL/6J mice, elevated circulating leptin, increased cardiomyocyte leptin and ObR expression, and activated myocardial signal transducer and activator of transcription-3 (STAT3). In leptin-deficient ob/ob mice, whether lean or obese, CAL caused increased hypertrophy and dilation, decreased contractility of the LV, and worsened survival relative to wildtype or leptin-repleted mice after CAL. In ob/ob mice, activation of cardiac STAT3 signalling after CAL is enhanced in the presence of leptin and parallels the induction of the STAT3-responsive genes, tissue-inhibitor of metalloproteinase-1 and heat shock protein-70.
  
  
  CONCLUSIONS
  These data demonstrate that HF increases ObR signalling in cardiomyocytes and that activation of ObR signalling improves functional outcomes in chronic ischaemic injury leading to HF.
authors.affiliation: Cardiovascular Institute, University of Pittsburgh Medical Center, 1750 Bioscience Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA. mcgaffinkr@upmc.edu
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: McGaffin
authors.forename: Cheuk-Kwan
authors.initials: CK
authors.lastname: Sun
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Rager
authors.forename: Lia C
authors.initials: LC
authors.lastname: Romano
authors.forename: Baobo
authors.initials: B
authors.lastname: Zou
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mathier
authors.forename: Robert M
authors.initials: RM
authors.lastname: O'Doherty
authors.forename: Charles F
authors.initials: CF
authors.lastname: McTiernan
authors.forename: Christopher P
authors.initials: CP
authors.lastname: O'Donnell
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000209:etiology; D006321:Heart / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D020738:Leptin / Q000172:deficiency / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000503:physiopathology*; D054411:Receptors, Leptin / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D016277:Ventricular Function, Left
chemical_list: D020738:Leptin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse