title: Beneficial effects of leptin treatment in a setting of cardiac dysfunction induced by transverse aortic constriction in mouse.
abstract: Leptin, is a 16 kDa pleiotropic peptide not only primarily secreted by adipocytes, but also produced by other tissues, including the heart. Controversy exists regarding the adverse and beneficial effects of leptin on the heart We analysed the effect of a non-hypertensive dose of leptin on cardiac function, [Ca2+]ihandling and cellular electrophysiology, which participate in the genesis of pump failure and related arrhythmias, both in control mice and in mice subjected to chronic pressure-overload by transverse aorta constriction. We find that leptin activates mechanisms that contribute to cardiac dysfunction under physiological conditions. However, after the establishment of pressure overload, an increase in leptin levels has protective cardiac effects with respect to rescuing the cellular heart failure phenotype. These beneficial effects of leptin involve restoration of action potential duration via normalization of transient outward potassium current and sarcoplasmic reticulum Ca2+content via rescue of control sarcoplasmic/endoplasmic reticulum Ca2+ATPase levels and ryanodine receptor function modulation, leading to normalization of Ca2+handling parameters.
  
  
  
  Leptin, is a 16 kDa pleiotropic peptide not only primary secreted by adipocytes, but also produced by other tissues, including the heart. Evidence indicates that leptin may have either adverse or beneficial effects on the heart. To obtain further insights, in the present study, we analysed the effect of leptin treatment on cardiac function, [Ca2+]ihandling and cellular electrophysiology, which participate in the genesis of pump failure and related arrhythmias, both in control mice and in mice subjected to chronic pressure-overload by transverse aorta constriction (TAC). Three weeks after surgery, animals received either leptin (0.36 mg kg-1day-1) or vehicle via osmotic minipumps for 3 weeks. Echocardiographic measurements showed that, although leptin treatment was deleterious on cardiac function in sham, leptin had a cardioprotective effect following TAC. [Ca2+]itransient in cardiomyocytes followed similar pattern. Patch clamp experiments showed prolongation of action potential duration (APD) in TAC and leptin-treated sham animals, whereas, following TAC, leptin reduced the APD towards control values. APD variations were associated with decreased transient outward potassium current and Kv4.2 and KChIP2 protein expression. TAC myocytes showed a higher incidence of triggered activities and spontaneous Ca2+waves. These proarrhythmic manifestations, related to Ca2+/calmodulin-dependent protein kinase II and ryanodine receptor phosphorylation, were reduced by leptin. The results of the present study demonstrate that, although leptin treatment was deleterious on cardiac function in control animals, leptin had a cardioprotective effect following TAC, normalizing cardiac function and reducing arrhythmogeneity at the cellular level.
authors.affiliation: Departament of Pharmacology, School of Medicine, Complutense University, Madrid, Spain.|UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.|Division of Clinical Pharmacology, Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Nieves
authors.identifier: 0000-0001-5338-7884
authors.initials: N
authors.lastname: Gómez-Hurtado
authors.affiliation: UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.|Institute of Biomedicine of Seville/CIBER-CV, Seville, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Domínguez-Rodríguez
authors.affiliation: UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Mateo
authors.affiliation: IdiPAZ Institute for Health Research/CIBER-CV, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Fernández-Velasco
authors.affiliation: IdiPAZ Institute for Health Research/CIBER-CV, Madrid, Spain.
authors.forename: Almudena
authors.identifier: 0000-0001-7029-2895
authors.initials: A
authors.lastname: Val-Blasco
authors.affiliation: Departament of Pharmacology, School of Medicine, Complutense University, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Aizpún
authors.affiliation: UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sabourin
authors.affiliation: UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Gómez
authors.affiliation: UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Jean-Pierre
authors.identifier: 0000-0002-9866-9081
authors.initials: JP
authors.lastname: Benitah
authors.affiliation: Departament of Pharmacology, School of Medicine, Complutense University, Madrid, Spain.|Biomedical Research Institute Alberto Sols/CIBER-CV, Madrid, Spain.
authors.forename: Carmen
authors.identifier: 0000-0002-0047-4674
authors.initials: C
authors.lastname: Delgado
mesh_terms: D000200:Action Potentials; D000818:Animals; D001024:Aortic Valve Stenosis / Q000188:drug therapy*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; C496755:Kcnip2 protein, mouse; D051605:Kv Channel-Interacting Proteins; D020738:Leptin; D019837:Ryanodine Receptor Calcium Release Channel; D051672:Shal Potassium Channels; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: heart failure; intracellular calcium; leptin